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Potential Interactions between Physical Agents and Therapeutic Drugs

Listed here are some potential interactions between physical agents used in rehabilitation and various pharmacologic agents. It is impossible to list all the possible relationships between the vast array of therapeutic drugs and the interventions used in physical therapy and occupational therapy. However, some of the more common interactions are identified here.
Desired Therapeutic Effect
Decreased pain, edema, and inflammation

Cryotherapy Cold/ice packs Ice massage Cold bath Vapocoolant sprays

Drugs with Complementary/ Synergistic Effects

Anti-inflammatory steroids (glucocorticoids); nonsteroidal anti-inflammatory analgesics (aspirin and similar NSAIDs) Skeletal muscle relaxants

Drugs with Antagonistic Effects

Peripheral vasodilators may exacerbate acute local edema

Other DrugModality Interactions

Muscle relaxation and decreased spasticity

Some forms of cryotherapy may produce local vasoconstriction that temporarily impedes diffusion of drugs to the site of inflammation Nonselective cholinergic ago- nists may stimulate the neuromuscular junction

Superficial and deep heat Local application Hot packs Paraffin Infrared Fluidotherapy Diathermy Ultrasound Systemic heat Large whirlpool Hubbard tank

Decreased muscle/joint pain and stiffness Decreased muscle spasms

NSAIDs; opioid analgesics; local anesthetics Skeletal muscle relaxants

Increased blood flow to improve tissue healing

Peripheral vasodilators

Nonselective cholinergic ago- nists may stimulate the neuromuscular junction Systemic vasoconstrictors (e.g., alpha-1 agonists) may decrease perfusion of peripheral tissues Severe hypotension may occur if systemic hot whirlpool is administered to patients taking peripheral vasodilators and some antihypertensive drugs (e.g., alpha-1 antagonists, nitrates, directacting vasodilators, calcium channel blockers) Antibacterial drugs generally increase cutaneous sensitivity to ultraviolet light (i.e., photosensitivity) Photosensitivity with antibacterial drugs

Decreased muscle/joint stiffness in large areas of the body

Opioid and nonopioid analgesics; skeletal muscle relaxants

Ultraviolet radiation

Increased wound healing

Various systemic and topical antibiotics

Management of skin disorders (acne, rashes)

Systemic and topical antibiotics and antiinflammatory steroids (glucocorticoids) Opioid and nonopioid analgesics Skeletal muscle relaxants

Many drugs may cause hypersensitivity reactions that result in skin rashes, itching Opioid antagonists (naloxone) Skeletal muscle relaxants

Decreased pain Transcutaneous electrical nerve stimulation (TENS) Functional neuromuscular electrical stimulation Increased skeletal muscle strength and endurance Decreased spasticity and muscle spasms

Nonselective cholinergic ago- nists may stimulate the neuromuscular junction

Common Drug Suffixes

Medications that are chemically and functionally similar often have generic names that share a common ending or suffix. Listed here are some drug classes that contain groups of drugs that share a common suffix. Please note that some members of a drug class may have a suffix that is different from the one indicated; for instance, not all benzodiazepines end with -epam or -olam.
Primary Indication or Desired Effect (Chapter in Parentheses)
Antihypertensive (21), congestive heart failure (24) Fungal infections (35) Sedative-hypnotic (6), antiseizure (9), anesthetic (11) Sedative-hypnotic (6), antianxiety (6), antiseizure (9), anesthetic (11) Antihypertensive (21), antianginal (22), antiarrhythmic (23), congestive heart failure (24) Osteoporosis (31) Bronchodilation (26) Bronchodilation (26) Antihypertensive (21), antianginal (22) Pain, inflammation (15)

Drug Class
Angiotensin-converting enzyme (ACE) inhibitors Azole antifungals Barbiturates


Common Examples
Captopril, enalapril

-azole -barbital

Fluconazole, miconazole Phenobarbital, secobarbital


-epam or -olam

Diazepam, temazepam, alprazolam, triazolam Metoprolol, propranolol

Beta blockers


Bisphosphonates Bronchodilators (adrenergic) Bronchodilators (xanthine derivatives) Calcium channel blockers (dihydropyridine group) Cyclooxygenase type 2 (COX-2) inhibitors Glucocorticoids

-dronate -erol -phylline -ipine

Alendronate, pamidronate Albuterol, pirbuterol Theophylline, aminophylline Nifedipine, nicardipine



-sone or -olone*

Cortisone, dexamethasone, prednisone, prednisolone, triamcinolone Cimetidine, ranitidine Ritonavir, saquinavir Pravastatin, simvastatin Lidocaine, bupivicaine

Anti-inflammatory (16, 29), immunosuppressants (37) Gastric ulcers (27) HIV infection (34) Hyperlipidemia (25) Local anesthetic (12), antiarrhythmics (23) Anticoagulants (25) Antidiabetic (type II diabetes mellitus) (32) Bacterial infections (33) Gastric ulcers (27) Bacterial infections (33) Bacterial infections (33)

Histamine H2-receptor blockers HIV protease inhibitors HMG-CoA reductase inhibitors (statins) Local anesthetics

-idine -avir -statin -caine

Low molecular-weight heparins Oral antidiabetics (sulfonylurea group) Penicillin antibiotics Proton pump inhibitors Tetracycline antibiotics Various other antibacterials

-parin -amide

Dalteparin, enoxaparin Chlorpropamide, tolbutamide

-cillin -prazole -cycline -micin or -mycin

Penicillin, ampicillin, amoxicillin Omeprazole, lansoprazole Tetracycline, doxycycline Streptomycin, gentamicin, erythromycin

*Some anabolic steroids also end with -olone, e.g., nandrolone, oxymetholone (Chapter 30). Some antibiotics ending with -mycin or rubicin are used as antineoplastics (Chapter 36).

Pharmacology in Rehabilitation
4th Edition

Contemporary Perspectives in Rehabilitation

Steven L. Wolf, PT, PhD, FAPTA, Editor-in-Chief
Pharmacology in Rehabilitation, 4th Edition Charles D. Ciccone, PT, PhD Vestibular Rehabilitation, 3rd Edition Susan J. Herdman, PT, PhD, FAPTA Modalities for Therapeutic Intervention, 4th Edition Susan L. Michlovitz, PT, PhD, CHT and Thomas P. Nolan, Jr., PT, MS, OCS Fundamentals of Musculoskeletal Imaging, 2nd Edition Lynn N. McKinnis, PT, OCS Wound Healing: Alternatives in Management, 3rd Edition Luther C. Kloth, PT, MS, CWS, FAPTA, and Joseph M. McCulloch, PT, PhD, CWS, FAPTA Evaluation and Treatment of the Shoulder: An Integration of the Guide to Physical Therapist Practice Brian J. Tovin, PT, MMSc, SCS, ATC, FAAOMPT and Bruce H. Greenfield, PT, MMSc, OCS Cardiopulmonary Rehabilitation: Basic Theory and Application, 3rd Edition Frances J. Brannon, PhD, Margaret W. Foley, RN, MN, Julie Ann Starr, PT, MS, CCS, and Lauren M. Saul, MSN, CCRN For more information on each title in the Contemporary Perspectives in Rehabilitation series, go to

Pharmacology in Rehabilitation
4th Edition
Charles D. Ciccone, PT, PhD
Professor Department of Physical Therapy School of Health Sciences and Human Performance Ithaca College Ithaca, New York

F. A. Davis Company 1915 Arch Street Philadelphia, PA 19103 Copyright 2007 by F. A. Davis Company Copyright 1990 and 1996 by F. A. Davis Company. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any from or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America Last digit indicates print number: 10 9 8 7 6 5 4 3 2 1 Publisher: Margaret Biblis Acquisitions Editor/Developmental Editor: Melissa Duffield Manager Art and Design: Carolyn OBrien As new scientific information becomes available through basic and clinical research, recommended treatments and drug threrapies undergo changes. The author and publisher have done everything possible to make this book accurate, up to date, and in accord with accepted standards at the time of publication. The author, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of the book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised always to check product information (package inserts) for changes and new information regarding dose and contraindications before administering any drug. Caution is especially urged when using new or infrequently ordered drugs. Library of Congress Cataloging-in-Publication Data Ciccone, Charles D., 1953 Pharmacology in rehabilitation / Charles D. Ciccone. 4th ed. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-0-8036-1377-5 ISBN-10: 0-8036-1377-6 1. Pharmacology. 2. Medical rehabilitation. I. Title. [DNLM: 1. Drug Therapy. 2. Pharmacokinetics. 3. Pharmacology. 4. WB 330 C568p 2007] RM301.C515 2007 615.1dc22


2006101581 Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by F. A. Davis Company for users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service, provided that the fee of $.10 per copy is paid directly to CCC, 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license by CCC, a separate system of payment has been arranged. The fee code for users of the Transactional Reporting Service is: 80361377/07 0 $.10

Dedicated to Penny, Kate, and Alex for providing constant faith, support, and inspiration.

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There are very peculiar ways in which one can mark time. We often do so by observing the rate at which our siblings, children, or grandchildren grow, especially when we are not in daily contact, or by how we inevitably underestimate the length of time transpired since we last encountered an old friend. In this context, it seems remarkable that over 13 years have transpired since I first discussed with Chuck Ciccone the prospects for a text on pharmacology for our Contemporary Perspectives in Rehabilitation. The realization that the first edition of Pharmacology in Rehabilitation appeared more than a decade ago is even more astounding. The basis for the genesis of such a book was founded on the belief that rehabilitation specialists received little formal training about drug interactions and how any single pharmacological agent could impact either treatment plans or outcomes. Chuck took it upon himself to generate a text that would address this educational and clinical shortcoming. The result is very clear. Pharmacology in Rehabilitation is the gold standard among all texts addressing this content for nonphysician rehabilitation specialists. So why is it important to create a fourth edition within one decade? Why is a more superficial compendium of information about drugs and their actions inadequate? The answer to these questions is directly related to the rapidly emerging responsibilities incumbent upon rehabilitation specialists. During the past 5 years, the advent of clinical doctoral programs in physical and occupational therapy has heralded a rapid transformation in these educational arenas. Several attributes now take on a meaning that previously might have been underappreciated. First, the label of doctor implies an expectation on the part of the consumer that the practitioner is the penultimate expert on providing an analysis and treatment plan for improving upon the pathology of any systems movement, whether muscle, joint, pulmonary, etc. Second, given the status associated with the professional label, there is an associated obligation on the part of the practitioner to address all aspects of the patients signs and symptoms. This obligation requires that the clinician differentiate patient responses to treatment from patient responses to pharmacy. As one physical therapist so astutely told me, her recognition that a patient was not responding to pain medication taken well above the specified dosage, in the absence of any evidence for malingering behavior, resulted in the subsequent detection and successful removal of a renal tumor. Third, as practitioners, the DPT or DOT now assumes a greater responsibility for keeping a contemporary knowledge base about the interface between treatment plan and concurrent synergies or exacerbations that might result from single or multiple medications taken by the patient. This collection of attributes can be best appreciated if the student is first informed and the clinician is educated about the most recent medications, their pharmokinetics, and the interactions they have with patients with specific diagnoses. Since the drug industry is arguably one of the most dynamic corporate structures in the world, changes in pharmacy occur at an alarmingly fast rate, one that will increase even more dramatically as transplants and the sequelae resulting from genetic engineering (as two examples) take on greater roles in medicine. Such rapid changes, then, call for contemporary and comprehensive updates in available information. Such updates must be presented in a manner that is compelling, yet easy to understand. Inclusive in this perception is the absolute requirement that the student or clinician be able to relate to the text meaningfully. Toward this important goal, the 4th edition of Pharmacology in Rehabilitation is designed to address rehabilitation relevance in every clinical chapter as well as to present important case histories to reinforce this relevance. New materials on agents used in or even as complementary and alternative medicines have been added. Moreover, we have made efforts to add to the appeal of the book through the addition of colorization, use of double columns, and encasing the text within a newly designed hard cover. These changes are in contradistinction to one standard that remains immutableDr. Ciccones remarkable gift for taking complex material and making it easy to understand.



For those clinicians who have in their possession early editions of this book, I invite you to compare your copy to the 4th edition as validation for the assertions made in this Foreword. We have not compromised the comprehensive nature of this volume in favor of a simpler approach to understanding pharmacology. We believe that the topic, by its very nature and from the implications inherent in its knowledge base, requires a comprehensive, yet userfriendly, delivery. This belief system remains unhindered in this latest edition; yet the problem-solving and evidence-based nature of the content is preserved and enhanced.

The thought of having a reference text for rehabilitation specialists was considered by us to be a unique concept 13 years ago. Today, many doctoral programs include pharmacology as a separate course or as an important component in teaching the rationale for treatment approaches and their assessment. There is much gratification to be gained from recognizing this transformation and in knowing that the content of this book contributes to the evolving maturation of our educational programs and our clinical services. Steven L. Wolf, PT, PhD, FAPTA Series Editor

In one sense, pharmacology can be considered a good news, bad news scenario. The good news is that exciting and innovative changes in drug therapy continue to occur at lightning speed. The bad news is that it is often difficult for health care practitioners to stay abreast of this rapidly changing field. Oftentimes, drug therapies that were considered state-of-the-art only a few years ago are now outdated and replaced by more contemporary treatments. Hence, the fourth edition of this text has been revised extensively to reflect the science and practice of pharmacology, with particular emphasis on how drug therapy impacts patients receiving physical rehabilitation. Efforts were made to use the peer-reviewed literature to obtain the most recent information on pharmacotherapeutics. This information has become incredibly accessible because of computerized databases such as PubMed and resources such as the FDA website. The volume of this information, however, is so extensive that I was often astounded by the number of articles on a given topic. It was certainly a challenge to condense this information into a meaningful format for busy students and clinicians. Nonetheless, I believe this edition is successful in presenting the most recent and pertinent details of pharmacotherapeutics and that it underscores the relevance of this topic to physical therapy and occupational therapy. As in previous editions, basic pharmacology concepts are addressed in the first section (Chapters 1 through 4), with subsequent chapters dealing with drug applications in specific diseases and pathological conditions. Chapters that deal with specific diseases begin with background information on each system or disorder, followed by detailed descriptions of the physiologic and pharmacologic actions of these drugs, their primary beneficial and adverse effect, and how drug therapy can impact physical rehabilitation. A new chapter on complementary and alternative medications (Chapter 38) has been added to this edition. This chapter complements the other chapters that deal with more traditional and conventional medications. This edition also has a new look, with many features added to help students and clinicians access this information more easily. Once again, I am pleased to present students and clinicians with a resource that might ultimately improve their ability to provide therapeutic interventions. Pharmacology continues to expand both in terms of the number of medications available to our patients, and in our understanding of how drugs can be used most effectively as part of a comprehensive health care regimen. It is essential that we understand the beneficial and adverse affects of medications commonly taken by our patients, and consider how we can capitalize on the beneficial effects while dealing with drug side effects. I hope this book will continue to serve as a primary resource on this topic, and that readers find this fourth edition interesting and useful. Charles D. Ciccone


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This edition is the culmination of the invaluable assistance and input from some very talented people. In particular, I want to thank Barbara MacDermott Costa, Linda D. Crane, John F. Decker, Mark Greve, Sandra B. Levine, Donald L. Merrill, Grace Minerbo, Peter Panus, and Jeffrey Rothman. I am deeply indebted to these individuals for their suggestions on previous editions. Without their help, it is unlikely that the fourth edition of this text would have ever become a reality. I would also like to thank Bonnie DeSombre, Fred Estabrook, and Cheryl Tarbell for their help in preparing various tables and figures appearing in this text. Finally, Steve Wolf, editor of the CPR series, has been a strong and consistent advocate for this book, and I thank him for his steadfast support and encouragement over the years. I also want to thank the staff at F. A. Davis Company for their help and proficiency in developing this text. In particular, Margaret Biblis and Melissa Duffield were instrumental in developing the fourth edition of this text, and for implementing most of the obvious changes in the design and presentation of this material. I cannot thank them enough for all their insight and expertise, and I am sure their efforts will be appreciated by everyone who uses this text.


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Reviewer List
Susan Sullivan Glenney, PT, MS Former Assistant Professor Department of Physical Therapy University of Hartford West Hartford, Connecticut Gary Gorniak, PT, PhD Director and Associate Professor Physical Therapy Program University of St. Augustine for Health Sciences St. Augustine, Florida Ellen Wruble Hakim, PT, DScPT, MS, CWS Assistant Professor Department of Physical Therapy and Rehabilitation Science University of Maryland School of Medicine Baltimore, Maryland Steven Raymond Tippett, PT, PhD, SCS, ATC Associate Professor Department of Physical Therapy and Health Science Bradley University Peoria, Illinois


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Section 1. General Principles of Pharmacology, 1
Chapter 1. Basic Principles of Pharmacology, 3
Drug Nomenclature, 4 Substitution of Generic Drugs for Brand-Name Products, 5 What Constitutes a Drug: Development and Approval of Therapeutic Agents, 5
Drug Approval Process, 5 Prescription Versus Over-the-Counter Medication, 7 Controlled Substances, 8

Drug Storage, 22
Storage Sites, 22 Adverse Consequences of Drug Storage, 23

Newer Techniques for Drug Delivery, 23

Controlled-Release Preparations, 23 Implanted Drug Delivery Systems, 23 Targeting Drug Delivery to Specific Cells and Tissues, 24

Chapter 3. Pharmacokinetics II: Drug Elimination, 29

Biotransformation, 29
Cellular Mechanisms of Drug Biotransformation, 29 Organs Responsible for Drug Biotransformation, 31 Enzyme Induction, 31

Basic Concepts in Drug Therapy, 8

Dose-Response Curves and Maximal Efficacy, 8 Potency, 9

Drug Excretion, 31 Drug Elimination Rates, 32

Clearance, 33 Half-Life, 33

Elements of Drug Safety, 10

Quantal Dose-Response Curves and the Median Effective Dose, 10 Median Toxic Dose, 10 Therapeutic Index, 11

Dosing Schedules and Plasma Concentration, 34 Variations in Drug Response and Metabolism, 34

Chapter 4. Drug Receptors, 41

Receptors Located on the Cells Surface, 41
Surface Receptors Linked Directly to Ion Channels, 41 Surface Receptors Linked Directly to Enzymes, 42 Surface Receptors Linked to Regulatory (G) Proteins: Role of the Second Messenger, 42

Chapter 2. Pharmacokinetics I: Drug Administration, Absorption, and Distribution, 13

Routes of Administration, 13
Enteral, 13 Parenteral, 15 Transdermal, 17

Intracellular Receptors, 44 Drug-Receptor Interactions, 44 Functional Aspects of Drug-Receptor Interactions, 45

Drug Selectivity and Receptor Subtypes, 45 Dose-Response, 46 Classification of Drugs: Agonist Versus Antagonist, 46 Competitive Versus Noncompetitive Antagonists, 46 Partial Agonists, 47 Mixed AgonistAntagonists and Inverse Agonists, 48

Drug Absorption and Distribution: Bioavailability, 17

Membrane Structure and Function, 17 Movement Across Membrane Barriers, 18 Active Transport, 20

Distribution of Drugs Within the Body, 21

Factors Affecting Distribution, 21 Volume of Distribution, 21




Receptor Regulation, 48
Receptor Desensitization and Down-Regulation, 48 Receptor Supersensitivity, 49

Special Consideration of Sedative-Hypnotic and Antianxiety Agents in Rehabilitation, 73 Case Study

Sedative-Hypnotic Drugs, 74

Nonreceptor Drug Mechanisms, 50

Section 2. Pharmacology of the Central Nervous System, 53

Chapter 5. General Principles of Central Nervous System Pharmacology, 55
CNS Organization, 55
Cerebrum, 55 Basal Ganglia, 55 Diencephalon, 56 Mesencephalon and Brainstem, 56 Cerebellum, 56 Limbic System, 57 Spinal Cord, 57

Chapter 7: Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome, 77
Depression, 77
Clinical Picture, 77 Pathophysiology of Depression, 78 Antidepressant Drugs, 79 Use of Antidepressants in Chronic Pain, 86

Treatment of Bipolar Disorder: Antimanic Drugs, 86

Bipolar Disorder, 86 Lithium, 86 Other Drugs Used in Bipolar Disorder, 87

The Blood-Brain Barrier, 57 CNS Neurotransmitters, 57

Acetylcholine, 58 Monoamines, 59 Amino Acids, 59 Peptides, 59 Other Transmitters, 59

Special Concerns in Rehabilitation Patients, 88 Case Study

Antidepressant Drugs, 89

Chapter 8. Antipsychotic Drugs, 93

Schizophrenia, 93 Neurotransmitter Changes in Schizophrenia, 94 Antipsychotic Mechanism of Action, 94 Antipsychotic Medications, 95
Traditional Antipsychotics, 95 Atypical Antipsychotics, 95

CNS Drugs: General Mechanisms, 60

Chapter 6. Sedative-Hypnotic and Antianxiety Agents, 65

Sedative-Hypnotic Agents, 65
Benzodiazepines, 65 Nonbenzodiazepines, 68

Pharmacokinetics, 96 Other Uses of Antipsychotics, 98 Problems and Adverse Effects, 98

Extrapyramidal Symptoms, 98

Pharmacokinetics, 69 Problems and Adverse Effects, 69

Residual Effects, 69 Tolerance and Physical Dependence, 69 Other Side Effects, 70

Nonmotor Effects, 100

Sedation, 100 Anticholinergic Effects, 100 Other Side Effects, 100

Antianxiety Drugs, 70
Benzodiazepines, 70 Buspirone, 71 Use of Antidepressants in Anxiety, 72 Other Antianxiety Drugs, 72 Problems and Adverse Effects, 72

Special Concerns in Rehabilitation Patients, 101 Case Study

Antipsychotic Drugs, 101



Chapter 9. Antiepileptic Drugs, 105

Classification of Epileptic Seizures, 105 Rationale for Drug Treatment, 107 Drugs Used to Treat Epilepsy, 107
Barbiturates, 107 Benzodiazepines, 107 Hydantoins, 108 Iminostilbenes, 109 Succinimides, 109 Valproic Acid, 109 Newer Second-Generation Agents, 110

Chapter 11. General Anesthetics, 135

General Anesthesia: Requirements, 135 Stages of General Anesthesia, 135 General Anesthetics: Classification and Use According to Route of Administration, 136 General Anesthetics: Specific Agents, 136
Inhalation Anesthetics, 136 Intravenous Anesthetics, 136

Pharmacokinetics, 139 Mechanisms of Action, 139 Adjuvants in General Anesthesia, 141

Preoperative Medications, 141 Neuromuscular Blockers, 141

Selection of a Specific Antiepileptic Agent, 111 Single-Drug Therapy Versus Drug Combinations in Epilepsy, 113 Pharmacokinetics, 113 Special Precautions During Pregnancy, 113 Treatment of Status Epilepticus, 113 Withdrawal of Antiseizure Medications, 114 Special Concerns in Rehabilitation Patients, 114 Case Study
Antiepileptic Drugs, 115

Special Concerns in Rehabilitation, 145 Case Study

General Anesthetics, 145

Chapter 12. Local Anesthetics, 149

Types of Local Anesthetics, 149 Pharmacokinetics, 150 Clinical Use of Local Anesthetics, 150 Mechanism of Action, 154 Differential Nerve Block, 155 Systemic Effects of Local Anesthetics, 156 Significance in Rehabilitation, 157 Case Study
Local Anesthetics, 157

Chapter 10. Pharmacological Management of Parkinson Disease, 119

Pathophysiology of Parkinson Disease, 119 Etiology of Parkinson Disease: Genetic and Environmental Factors, 120 Therapeutic Agents in Parkinsonism, 121
Levodopa, 122 Other Drugs Used to Treat Parkinson Disease, 126

Section 3. Drugs Affecting Skeletal Muscle, 161

Chapter 13. Skeletal Muscle Relaxants, 163
Increased Muscle Tone: Spasticity Versus Muscle Spasms, 163 Specific Agents Used to Produce Skeletal Muscle Relaxation, 164 Agents Used to Treat Muscle Spasms, 164
Diazepam, 164 Polysynaptic Inhibitors, 165

Clinical Course of Parkinson Disease: When to Use Specific Drugs, 129 Neurosurgical Interventions in Parkinson Disease, 129 Special Considerations for Rehabilitation, 130 Case Study
Anti-Parkinson Drugs, 131



Agents Used to Treat Spasticity, 166

Baclofen, 167 Intrathecal Baclofen, 168 Dantrolene Sodium, 169 Diazepam, 170 Gabapentin, 170 Tizanidine, 171

Chapter 15. Nonsteroidal Anti-Inflammatory Drugs, 199

Aspirin and Other NSAIDs: General Aspects, 199 Prostaglandins, Thromboxanes, and Leukotrienes, 200
Eicosanoid Biosynthesis, 200 Role of Eicosanoids in Health and Disease, 201

Use of Botulinum Toxin as a Muscle Relaxant, 171 Pharmacokinetics, 174 Special Concerns in Rehabilitation Patients, 174 Case Study
Muscle Relaxants, 175

Mechanism of NSAID Action: Inhibition of Prostaglandin and Thromboxane Synthesis, 202 Aspirin: Prototypical NSAID, 203 Clinical Applications of Aspirinlike Drugs, 203
Treatment of Pain and Inflammation, 203 Treatment of Fever, 204 Treatment of Vascular Disorders, 204 Prevention of Cancer, 204

Section 4. Drugs Used to Treat Pain and Inflammation, 181

Chapter 14. Opioid Analgesics, 183
Source of Opioid Analgesics, 183 Endogenous Opioid Peptides and Opioid Receptors, 184
Endogenous Opioids, 184 Opioid Receptors, 184

Problems and Adverse Effects of Aspirinlike Drugs, 204

Gastrointestinal Problems, 204 Other Side Effects, 205

Comparison of Aspirin with Other NSAIDs, 206 COX-2 Selective Drugs, 209
COX-2 Drugs and the Risk of Heart Attack and Stroke, 210

Classification of Specific Agents, 185 Pharmacokinetics, 187 Mechanism of Action, 188

Effect of Opioids on the CNS, 188 Effect of Opioids on CNS Synapses, 188 Peripheral Effects of Opioids, 190

Acetaminophen, 210 Pharmacokinetics of NSAIDs and Acetaminophen, 211 Special Concerns in Rehabilitation Patients, 212 Case Study
Nonsteroidal Anti-Inflammatory Drugs, 212

Clinical Applications, 190

Treatment of Pain, 190 Use of Opioids in Patient-Controlled Analgesia, 191 Other Opioid Uses, 191

Problems and Adverse Effects, 192 Concepts of Addiction, Tolerance, and Physical Dependence, 192
Tolerance, 192 Physical Dependence, 193 Tolerance and Dependence During Therapeutic Opioid Use, 193 Pharmacological Treatment of Opioid Addiction, 193

Chapter 16. Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis, 217

Rheumatoid Arthritis, 217
Immune Basis for Rheumatoid Arthritis, 218 Overview of Drug Therapy in Rheumatoid Arthritis, 219 Nonsteroidal Anti-Inflammatory Drugs, 219 Glucocorticoids, 221 Disease-Modifying Antirheumatic Drugs, 222 DMARD Combinations Used in Rheumatoid Arthritis, 228 Dietary Implications for Rheumatoid Arthritis, 229

Special Concerns in Rehabilitation Patients, 194 Case Study

Opioid Analgesics, 195



Osteoarthritis, 229
Acetaminophen and NSAIDs, 230 Viscosupplementation, 230 Glucosamine and Chondroitin Sulfate, 230

Functional Aspects of the Sympathetic and Parasympathetic Divisions, 254

Function of the Adrenal Medulla, 255 Autonomic Integration and Control, 256 Autonomic Neurotransmitters, 257
Acetylcholine and Norepinephrine, 257 Other Autonomic Neurotransmitters, 257

Special Concerns for Antiarthritic Drug Therapy in Rehabilitation Patients, 231 Case Study
Rheumatoid Arthritis, 232

Chapter 17. Patient-Controlled Analgesia, 237

Pharmacokinetic Basis for PCA, 237 PCA Dosing Strategies and Parameters, 238
Loading Dose, 238 Demand Dose, 238 Lockout Interval, 238 1- and 4-Hour Limits, 238 Background Infusion Rate, 239 Successful Versus Total Demands, 239

Autonomic Receptors, 258 Cholinergic Receptors, 258

Adrenergic Receptors, 259

Pharmacologic Significance of Autonomic Receptors, 261

Chapter 19. Cholinergic Drugs, 263

Cholinergic Receptors, 263 Cholinergic Stimulants, 264
Direct-Acting Cholinergic Stimulants, 264 Indirect-Acting Cholinergic Stimulants, 264 Clinical Applications of Cholinergic Stimulants, 266 Adverse Effects of Cholinergic Stimulants, 267

Types of Analgesics Used for PCA, 239 Administration Routes During PCA, 240
Intravenous PCA, 240 Epidural PCA, 241 Transdermal PCA, 241 Regional PCA, 242

Anticholinergic Drugs, 268

Source and Mechanism of Action of Antimuscarinic Anticholinergic Drugs, 268 Clinical Applications of Antimuscarinic Drugs, 268 Side Effects of Anticholinergic Drugs, 271

PCA Pumps, 242 Comparison of PCA to Traditional Methods of Analgesic Administration, 243 Problems and Side Effects of PCA, 245
Pharmacologic Side Effects, 245 Problems with PCA Delivery, 245

Chapter 20. Adrenergic Drugs, 273

Adrenergic Receptor Subclassifications, 273 Adrenergic Agonists, 274
Alpha Agonists, 275 Beta Agonists, 276 Drugs with Mixed Alpha- and Beta-Agonist Activity, 278

Special Concerns for PCA in Rehabilitation Patients, 246 Case Study

Patient-Controlled Analgesia, 247

Adrenergic Antagonists, 279

Section 5. Autonomic and Cardiovascular Pharmacology, 251

Chapter 18. Introduction to Autonomic Pharmacology, 253
Anatomy of the Autonomic Nervous System: Sympathetic and Parasympathetic Divisions, 253
Preganglionic and Postganglionic Neurons, 253 Sympathetic Organization, 254 Parasympathetic Organization, 254

Alpha Antagonists, 279 Beta Antagonists, 281 Other Drugs That Inhibit Adrenergic Neurons, 284

Chapter 21. Antihypertensive Drugs, 287

Normal Control of Blood Pressure, 288 Pathogenesis of Hypertension, 288
Essential Versus Secondary Hypertension, 288 Possible Mechanisms in Essential Hypertension, 288



Drug Therapy, 289 Diuretics, 290

Mechanism of Action and Rationale for Use, 290 Classification of Diuretics, 291 Adverse Effects of Diuretics, 292

Specific Agents, 311 Adverse Side Effects, 312

Use of Anticoagulants in Angina Pectoris, 312 Treatment of Specific Types of Angina Pectoris, 313
Stable Angina, 314 Variant Angina (Prinzmetal Ischemia), 314 Unstable Angina, 315

Sympatholytic Drugs, 292

Beta Blockers, 292 Alpha Blockers, 293 Presynaptic Adrenergic Inhibitors, 294 Centrally Acting Agents, 295 Ganglionic Blockers, 295

Nonpharmacologic Management of Angina Pectoris, 315 Special Concerns in Rehabilitation Patients, 316 Case Study
Antianginal Drugs, 316

Vasodilators, 296
Mechanism of Action and Rationale for Use, 296 Specific Agents, 296 Adverse Effects, 297

Inhibition of the Renin-Angiotensin System, 297

Mechanism of Action and Rationale for Use, 297 Specific Agents, 298 Adverse Effects, 298

Chapter 23. Treatment of Cardiac Arrhythmias, 321

Cardiac Electrophysiology, 321
Cardiac Action Potentials, 321 Normal Cardiac Rhythm, 322 Normal Conduction of the Cardiac Action Potential, 322

Calcium Channel Blockers, 299

Specific Agents, 299 Adverse Effects, 299

Mechanisms of Cardiac Arrhythmias, 323 Types of Arrhythmias, 324 Classification of Antiarrhythmic Drugs, 324
Class I: Sodium Channel Blockers, 324 Class II: Beta Blockers, 326 Class III. Drugs That Prolong Repolarization, 326 Class IV: Calcium Channel Blockers, 327

Stepped-Care Approach to Hypertension, 300 Nonpharmacologic Treatment of Hypertension, 300 Special Concerns in Rehabilitation Patients, 301 Case Study
Hypertension, 301

Other Drugs Used to Treat Arrhythmias, 327 Nonpharmacologic Treatment of Arrhythmias, 327 Special Concerns in Rehabilitation Patients, 328 Case Study
Antiarrhythmic Drugs, 328

Chapter 22. Treatment of Angina Pectoris, 307

Drugs Used to Treat Angina Pectoris, 308 Organic Nitrates, 308
Mechanism of Action and Rationale for Use, 308 Specific Agents, 309 Adverse Side Effects of Nitrates, 310

Chapter 24. Treatment of Congestive Heart Failure, 331

Pathophysiology of Congestive Heart Failure, 331
Vicious Cycle of Heart Failure, 331 Congestion in Left and Right Heart Failure, 333

Beta-Adrenergic Blockers, 310

Mechanism of Action and Rationale for Use, 310 Specific Agents, 310 Adverse Side Effects, 311

Pharmacotherapy, 334 Drugs That Increase Myocardial Contraction Force (Positive Inotropic Agents), 334

Calcium Channel Blockers, 311

Mechanism of Action and Rationale for Use, 311



Digitalis, 334 Other Positive Inotropic Agents, 338

Antihistamines, 370 Mucolytics and Expectorants, 373

Agents That Decrease Cardiac Workload, 339

Drugs Affecting the Renin-Angiotensin System, 339 Beta Blockers, 340 Diuretics, 341 Vasodilators, 342

Drugs Used to Maintain Airway Patency in Obstructive Pulmonary Disease, 373

Beta-Adrenergic Agonists, 373 Xanthine Derivatives, 376 Anticholinergic Drugs, 377 Glucocorticoids, 378 Cromones, 379 Leukotriene Inhibitors, 380

Summary of Drug Therapy, 342 Special Concerns in Rehabilitation Patients, 343 Case Study
Congestive Heart Failure, 343

Treatment of Bronchial Asthma, 380

Pathophysiology of Bronchial Asthma, 380 Long-Term Management of Asthma, 381

Chapter 25. Treatment of Coagulation Disorders and Hyperlipidemia, 347

Normal Mechanism of Blood Coagulation, 347
Clot Formation, 348 Clot Breakdown, 349

Treatment of Reversible Bronchospasm in COPD, 382 Treatment of Respiratory Problems in Cystic Fibrosis, 382 Special Concerns in Rehabilitation Patients, 383 Case Study
Respiratory Drugs, 384

Drugs Used to Treat Overactive Clotting, 349

Anticoagulants, 349 Antithrombotic Drugs, 352 Thrombolytic Drugs, 354

Treatment of Clotting Deficiencies, 356

Hemophilia, 356 Deficiencies of Vitamin K-Dependent Clotting Factors, 357 Antifibrinolytics, 357

Chapter 27. Gastrointestinal Drugs, 389

Drugs Used to Control Gastric Acidity and Secretion, 389
Antacids, 389 H2 Receptor Blockers, 390 Proton Pump Inhibitors, 391 Treatment of H. Pylori Infection in Gastric Ulcer Disease, 392 Other Agents Used to Control and Treat Gastric Ulcers, 393

Agents Used to Treat Hyperlipidemia, 357

HMG-CoA Reductase Inhibitors (Statins), 358 Fibric Acids, 359 Other Lipid-Lowering Agents, 360 Adverse Effects of Antihyperlipidemia Agents, 360

Special Concerns in Rehabilitation Patients, 361 Case Study

Clotting Disorders, 362

Antidiarrheal Agents, 393

Opioid Derivatives, 394 Adsorbents, 395 Bismuth Salicylate, 395 Miscellaneous Agents Used to Treat Diarrhea, 395

Section 6. Respiratory and Gastrointestinal Pharmacology, 367

Chapter 26. Respiratory Drugs, 369
Drugs Used to Treat Respiratory Tract Irritation and Control Respiratory Secretions, 369
Antitussives, 369 Decongestants, 370

Laxatives and Cathartics, 395

Rationale for Use, 395 Specific Agents and Mechanism of Action, 396 Adverse Effects, 397

Miscellaneous Gastrointestinal Drugs 397

Digestants, 397 Emetics, 397 Antiemetics, 397 Cholelitholytic Agents, 397



Special Concerns in Rehabilitation Patients, 398 Case Study

Gastrointestinal Drugs, 398

Mineralocorticoids, 426
Regulation of Mineralocorticoid Secretion, 426 Mechanism of Action and Physiologic Effects of Mineralocorticoids, 426 Therapeutic Use of Mineralocorticoid Drugs, 428 Adverse Effects of Mineralocorticoid Agonists, 428 Mineralocorticoid Antagonists, 428

Section 7. Endocrine Pharmacology, 401

Chapter 28. Introduction to Endocrine Pharmacology, 403
Primary Endocrine Glands and Their Hormones, 403
Hypothalamus and Pituitary Gland, 403 Thyroid Gland, 405 Parathyroid Gland, 406 Pancreas, 406 Adrenal Gland, 406 Gonads, 407

Special Concerns of Adrenal Steroid Use in Rehabilitation Patients, 429 Case Study
Adrenocorticosteroids, 430

Chapter 30. Male and Female Hormones, 435

Androgens, 435
Source and Regulation of Androgen Synthesis, 435 Physiologic Effects of Androgens, 437

Endocrine Physiology and Pharmacology, 407

Hormone Chemistry, 407 Synthesis and Release of Hormones, 407 Feedback Control Mechanisms in Endocrine Function, 408 Hormone Transport, 408 Hormone Effects on the Target Cell, 409

Pharmacologic Use of Androgens, 437

Clinical Use of Androgens, 437 Specific Agents, 438 Adverse Effects of Clinical Androgen Use, 439 Antiandrogens, 440

Androgen Abuse, 440

Nature of Androgen Abuse, 440 Effects of Androgens on Athletic Performance, 442 Adverse Effects of Androgen Abuse, 442

Clinical Use of Endocrine Drugs, 411

Chapter 29. Adrenocorticosteroids, 415

Steroid Synthesis, 415 Glucocorticoids, 417
Role of Glucocorticoids in Normal Function, 417 Mechanism of Action of Glucocorticoids, 417 Physiologic Effects of Glucocorticoids, 418

Estrogen and Progesterone, 443

Effects of Estrogen and Progesterone on Sexual Maturation, 443 Regulation and Effects of Hormonal Synthesis During the Menstrual Cycle, 443 Female Hormones in Pregnancy and Parturition, 445

Pharmacologic Use of Estrogen and Progesterone, 445

Conditions Treated with Estrogen and Progesterone, 445 Specific Agents, 446 Adverse Effects of Estrogen and Progesterone, 447 Selective Estrogen Receptor Modulators, 448 Antiestrogens, 449 Antiprogestins, 449

Therapeutic Glucocorticoid Agents, 421 Clinical Uses of Glucocorticoids, 421

Glucocorticoid Use in Endocrine Conditions, 421 Use in Nonendocrine Conditions, 421

Adverse Effects of Glucocorticoids, 423

Adrenocortical Suppression, 423 Drug-Induced Cushing Syndrome, 423 Breakdown of Supporting Tissues, 425 Other Adverse Effects, 425

Hormonal Contraceptives, 450

Types of Contraceptive Preparations, 450 Mechanism of Contraceptive Action, 452 Adverse Effects of Hormonal Contraceptives, 452

Drugs That Inhibit Adrenocortical Hormone Biosynthesis, 426

Case Study
Male and Female Hormones, 453



Special Concerns of Sex Hormone Pharmacology in Rehabilitation Patients 454

Use of Insulin in Diabetes Mellitus, 483

Therapeutic Effects and Rationale for Use, 483 Insulin Preparations, 483 Administration of Insulin, 485 Intensive Insulin Therapy, 485 Adverse Effects of Insulin Therapy, 486

Chapter 31. Thyroid and Parathyroid Drugs: Agents Affecting Bone Mineralization, 459
Function of the Thyroid Gland, 459
Synthesis of Thyroid Hormones, 459 Regulation of Thyroid Hormone Release, 461 Physiologic Effects of Thyroid Hormones, 461 Mechanism of Action of Thyroid Hormones, 461

Oral Antidiabetic Drugs, 486

Sulfonylureas, 487 Other Orally Active Drugs, 488

Other Drugs Used in the Management of Diabetes Mellitus, 488

Glucagon, 488 Glucagon-like Peptide 1, 488 Immunosuppressants, 489 Aldose Reductase Inhibitors, 489

Treatment of Thyroid Disorders 462

Hyperthyroidism, 462 Hypothyroidism, 463

Function of the Parathyroid Glands, 464

Parathyroid Hormone, 465

Regulation of Bone Mineral Homeostasis, 465 Pharmacologic Control of Bone Mineral Homeostasis, 466
Calcium Supplements, 467 Vitamin D, 469 Bisphosphonates, 469 Calcitonin, 469 Estrogen Therapy, 470 Other Agents That Promote Bone Mineral Content, 470

Nonpharmacologic Intervention in Diabetes Mellitus, 489

Dietary Management and Weight Reduction, 489 Exercise, 490 Tissue Transplants and Gene Therapy, 490

Significance of Diabetes Mellitus in Rehabilitation, 490 Case Study

Diabetes Mellitus, 491

Special Concerns in Rehabilitation Patients, 471 Case Study

Agents Affecting Bone Mineral Metabolism, 471

Section 8. Chemotherapy of Infectious and Neoplastic Diseases, 497

Chapter 33. Treatment of Infections I: Antibacterial Drugs, 499
Bacteria: Basic Concepts, 499
Bacterial Structure and Function, 499 Pathogenic Effects of Bacteria, 500 Bacterial Nomenclature and Classification, 500

Chapter 32. Pancreatic Hormones and the Treatment of Diabetes Mellitus, 477
Structure and Function of the Endocrine Pancreas, 477 Insulin, 477
Cellular Mechanism of Insulin Action, 478

Treatment of Bacterial Infections: Basic Principles, 500

Spectrum of Antibacterial Activity, 500 Bactericidal Versus Bacteriostatic Activity, 500

Glucagon, 479 Control of Insulin and Glucagon Release, 480 Diabetes Mellitus, 480
Type 1 Diabetes, 481 Type 2 Diabetes, 481 Effects and Complications of Diabetes Mellitus, 482

Basic Mechanisms of Antibacterial Drugs, 501

Inhibition of Bacterial Cell Wall Synthesis and Function, 501 Inhibition of Bacterial Protein Synthesis, 502 Inhibition of Bacterial DNA/RNA Synthesis and Function, 502



Specific Antibacterial Agents 503 Antibacterial Drugs That Inhibit Bacterial Cell Wall Synthesis and Function 503
Penicillins, 503 Cephalosporins, 505 Other Agents That Inhibit Bacterial Cell Wall Synthesis, 505 Use of Beta-Lactamase Inhibitors, 506

Specific Antiviral Drugs, 525

Acyclovir and Valacyclovir, 527 Amantadine and Rimantadine, 527 Cidofovir, 528 Docosanol, 528 Enfuvirtide, 528 Famciclovir and Penciclovir, 528 Fomivirsen, 529 Foscarnet, 529 Ganciclovir and Valganciclovir, 529 Imiquimod, 529 Trifluridine, 530 Oseltamivir and Zanamivir, 530 Protease Inhibitors, 530 Reverse Transcriptase Inhibitors, 531 Ribavirin, 532 Vidarabine, 533

Drugs That Inhibit Bacterial Protein Synthesis 507

Aminoglycosides, 507 Erythromycin and Other Macrolides, 508 Tetracyclines, 508 Other Agents That Inhibit Bacterial Protein Synthesis, 509

Drugs That Inhibit Bacterial DNA/RNA Synthesis and Function, 510

Aminosalicylic Acid, 510 Clofazimine, 510 Dapsone, 511 Ethambutol, 511 Fluoroquinolones, 511 Metronidazole, 511 Mupirocin, 512 Rifampin, 512 Sulfonamides, 512 Trimethoprim, 513

Viral Resistance, 533 Interferons, 533

Synthesis and Cellular Effects of Interferons, 534 Pharmacologic Applications of Interferons, 535 Adverse Effects of Interferons, 535

Control of Viral Infection with Vaccines, 535 HIV and the Treatment of AIDS, 536
Inhibition of HIV Proliferation in Infected Individuals, 537 Anti-HIV Drug Combinations: Use of Highly Active Antiretroviral Therapy, 537 HIV Vaccines, 538 Management of Opportunistic Infections, 539

Other Antibacterial Drugs, 513

Capreomycin, 513 Daptomycin, 513 Isoniazid, 513 Methenamine, 513 Nitrofurantoin, 513 Pyrazinamide, 514

Relevance of Antiviral Chemotherapy in Rehabilitation Patients, 540 Case Study

Antiviral Drugs, 541

Clinical Use of Antibacterial Drugs: Relationship to Specific Bacterial Infections, 514 Resistance to Antibacterial Drugs, 514 Special Concerns in Rehabilitation Patients, 518 Case Study
Antibacterial Drugs, 519

Chapter 35. Treatment of Infections III: Antifungal and Antiparasitic Drugs, 545
Antifungal Agents, 545
Systemic Antifungal Agents, 546 Topical Antifungal Agents, 550

Chapter 34. Treatment of Infections II: Antiviral Drugs, 523

Viral Structure and Function, 523
Classification of Viruses, 523 Characteristics of Viruses, 523 Viral Replication, 524

Antiprotozoal Agents, 551

Antimalarial Agents, 551 Drugs Used to Treat Protozoal Infections in the Intestines and Other Tissues, 555 Other Antiprotozoal Drugs, 557

Anthelmintics, 557



Albendazole, 557 Diethylcarbamazine, 558 Ivermectin, 558 Mebendazole, 559 Niclosamide, 559 Oxamniquine, 559 Piperazine Citrate, 559 Praziquantel, 559 Pyrantel Pamoate, 559 Thiabendazole, 559

Chapter 37. Immunomodulating Agents, 591

Overview of the Immune Response, 591 Pharmacologic Suppression of the Immune Response, 593 Specific Immunosuppresive Agents, 593
Azathioprine, 593 Cyclophosphamide, 595 Cyclosporine, 595 Glucocorticoids, 596 Methotrexate, 596 Mycophenolate Mofetil, 597 Sulfasalazine, 597 Sirolimus, 597 Tacrolimus, 598 Other Methods of Immunosuppression, 598

Significance of Antifungal and Antiparasitic Drugs in Rehabilitation, 560 Case Study

Antifungal Drugs, 560

Chapter 36. Cancer Chemotherapy, 565

General Principles, 565
Cytotoxic Strategy, 565 Cell-CycleSpecific Versus Cell-CycleNonspecific Drugs, 566 Concepts of Growth Fraction and Total Cell Kill, 566 Prevalence and Management of Adverse Effects, 566

Immunostimulants, 599
Bacille Calmette-Gurin, 600 Immune Globulin, 600 Levamisole, 600

Other Immunomodulators, 600 Significance of Immunomodulating Agents in Rehabilitation, 601 Case Study
Immunomodulating Agents, 601

Specific Drugs, 568

Alkylating Agents, 568 Antimetabolites, 569 Antibiotics, 569 Plant Alkaloids, 569 Hormones, 573 Biologic Response Modifiers, 577 Heavy Metal Compounds, 579 Aspirin and Other NSAIDs, 580 Tyrosine Kinase Inhibitors, 580 Miscellaneous Agents, 580

Chapter 38. Complementary and Alternative Medications, 605

Unique Aspects of CAMs, 605
Misconceptions about CAM Safety, 605 Failure to Report CAM Use, 606 Lack of Standards for Quality and Purity of CAMs, 606 Delayed Use of Conventional Medications, 606

Combination Chemotherapy, 582 Use of Anticancer Drugs with Other Treatments, 582 Success of Anticancer Drugs, 583 Resistance to Cancer Chemotherapy Drugs, 584 Future Perspectives, 585 Implications of Cancer Chemotherapy in Rehabilitation Patients, 586 Case Study
Cancer Chemotherapy, 586

Potential Adverse Effects of CAMs, 606 Specific CAMs, 607

Bee Venom, 607 Echinacea, 607 Garlic, 607 Ginger, 609 Ginkgo biloba, 609 Ginseng, 609 Glucosamine and Chondroitin, 609 Kava, 609 Melatonin, 610 Saw Palmetto, 610 St. Johns Wort, 610



Valerian, 610

Vitamins and Minerals, 611

Vitamins, 611 Minerals, 614

Appendix A: Drugs Administered by Iontophoresis and Phonophoresis, 619 Appendix B: Use of the Physicians Desk Reference, 621 Appendix C: Drugs of Abuse, 623 Glossary, 625 Index, 633

Special Concerns in Rehabilitation Patients, 614 Case Study

Complementary and Alternative Medications, 615


General Principles of Pharmacology

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Basic Principles of Pharmacology

Pharmacology is the study of drugs. In its broadest definition, a drug can be described as any substance that, when taken into a living organism, may modify one or more of its functions.28 In this sense, a drug includes any substance that alters physiologic function in the organism, regardless of whether the effect is beneficial or harmful. In terms of clinical pharmacology, it has traditionally been the beneficial or therapeutic effects that have been of special interest. Throughout history, certain naturally occurring chemicals have been used to relieve pain or treat disease in humans. Within the past century, the use of natural, semisynthetic, and synthetic chemical agents has expanded to the point where many diseases can be prevented or cured, and the general health and well-being of many individuals has dramatically improved through therapeutic drug use. Because of the extensive clinical use of therapeutic medications, members of the medical community must have some knowledge of the basic types of drugs and the mechanisms of their actions. Although this has always been true for individuals who prescribe and administer drugs (i.e., physicians and nurses), it is now recognized that members of other health-related professions must have a fundamental knowledge of pharmacology. An understanding of basic drug mechanisms can help practitioners such as physical therapists, occupational therapists, and other rehabilitation specialists better understand a patients response to the drug. In addition, the knowledge of how certain rehabilitative procedures may interact with medications is helpful in getting an optimal response in the patients drug and therapy treatment. For instance, scheduling the patient for therapy when certain drugs reach their peak effect may improve the therapy session dramatically. This may be true for drugs that decrease pain (analgesics) or improve the patients motor skills (anti-Parkinson drugs). Conversely, some therapy sessions that require the patients active participation may be rendered useless if scheduled when medications such as sedatives reach their peak effect. Also, any adverse responses occurring due to direct interaction between the therapy treatment and certain medications may be avoided or controlled by understanding a drugs pharmacologic aspects. For example, a patient who is taking a peripheral vasodilator may experience a profound decrease in blood pressure when he or she is placed in a hot whirlpool. By understanding the implications of such an interaction, the therapist can be especially alert for any detrimental effects on the patient, or they may institute a different therapy treatment for them. In order to help the reader have a more focused approach to the study of drugs, pharmacology is often divided into several areas of interest (Fig. 11). Pharmacotherapeutics is the area of pharmacology that refers to the use of specific drugs to prevent, treat, or diagnose a disease. For the purposes of this text, the effects of drugs on humans will be of primary concern, with animal pharmacology mentioned only in reference to drug testing and research in animals. When drugs are used therapeutically in humans, the way that the body interacts with the drug and what specific effect it has on an individual must be known. Consequently, pharmacotherapeutics is divided into two functional areas: pharmacokinetics and pharmacodynamics (see Fig. 11). Pharmacokinetics is the study of how the body deals with the drug in terms of the way it is absorbed, distributed, and eliminated.

SECTION 1 General Principles of Pharmacology









Systemic Effects

Cellular Effects

FIGURE 11 Areas of study within pharmacology.

Pharmacodynamics is the analysis of what the drug does to the body, including the mechanism by which the drug exerts its effect. In this text, the basic principles of pharmacokinetics will be outlined in Chapters 2 and 3, and the pharmacodynamics and pharmacokinetics of specific drugs will be discussed in their respective chapters. Toxicology is the study of the harmful effects of chemicals. Although it can be viewed as a subdivision of pharmacology, toxicology has evolved into a separate area of study because of the scope of all the therapeutic agents adverse effects as well as environmental toxins and poisons. However, because virtually every medication can produce adverse effects, a discussion of toxicology must be included in pharmacotherapeutics. For the purposes of this text, discussions of drug toxicity are limited to the unwanted effects that occur when therapeutic drugs reach excessively high (toxic) levels. The toxic side effects of individual drugs are covered in the chapters describing the therapeutic effects of that drug.

Pharmacy deals with the preparation and dispensing of medications. Although pharmacy is also frequently considered a subdivision of pharmacology, this area has evolved into a distinct professional discipline. Care must be taken not to use the terms pharmacy and pharmacology interchangeably, because these are quite different areas of study.

Drug Nomenclature
One of the most potentially confusing aspects of pharmacology is the variety of names given to different drugs or even to the same compound. Students of pharmacology, as well as clinicians, are often faced with myriad terms representing the same drug.14,17 Many problems in drug terminology arise from the fact that each drug can be identified according to its chemical, generic, or trade name12 (Table 11). Chemical names refer to the specific compounds structure and are usually fairly long and cumbersome. The generic name

Table 11


Generic (Nonproprietary) Acetaminophen Levodopa Phenobarbital Diazepam Trade/Brand-Name (Proprietary) Tylenol, Panadol, many others Larodopa Luminal, Eskabarb Valium

N-Acetyl-p-aminophenol 3,4-Dihydroxyphenyl-L-alanine 5,5-Phenylethylbarbituric acid 7-Chloro-1,3-dihydro-1-methyl5-phenyl-2H-1,4-benzodiazepin-2-one

Chapter 1 Basic Principles of Pharmacology

(also known as the official or nonproprietary name) tends to be somewhat shorter and is often derived from the chemical name. A trade name (also known as the brand name) is assigned to the compound by the pharmaceutical company and may or may not bear any reference at all to the chemical and generic terminology. An additional problem with trade names is that several manufacturers may be marketing the same compound under different names, thus adding to the confusion. If there is no existing patent for that compound or if the patent has expired, the same drug may be marketed by separate drug companies.24 For practical purposes, the generic name is often the easiest and most effective way to refer to a drug, and this terminology will be used frequently in this text. Drug nomenclature is also a source of confusion and potential errors in medication use, especially when different drugs have names that look or sound alike.14 It has been estimated, for example, that up to 25 percent of all medication errors are caused by name confusion.2,13 This fact seems especially true for drugs with similar brand names.14 Consider, for example, the confusion that could occur when trying to differentiate between the following three brand-name products: Celebrex, Cerebryx, and Celexa.14 These three brand names correspond with an analgesic (see Chapter 15), an antiseizure drug (see Chapter 9) and an antidepressant (see Chapter 7), respectively. Despite their similar brand names, these three products represent three distinct pharmacologic classes that are used in very different clinical situations. Hence, practitioners need to be especially careful when documenting the use of specific medications, and make sure that the correct drug name is used to identify each product.

profile (drug absorption, plasma levels, and so forth), and the same therapeutic effects as the brand-name drug.3 If such testing is done, the two drugs are said to be bioequivalent.7 Unless bioequivalence is established, however, it can only be assumed that substituting a generic drug will produce therapeutic effects that are similar to the brand-name drug. Likewise, establishing bioequivalence of a generic form does not guarantee that a given patient will not experience different effects from the generic form compared to the brand-name product. That is, certain patients might simply respond differently to a the generic form of a drug because of individual differences in their ability to absorb and metabolize certain generic products, even if these products have been shown to be similar to their brandname counterpart during bioequivalence testing. This fact seems especially true for drugs that tend to produce a wider range of therapeutic and adverse effects when tested in a specific patient, or within a group of patients (i.e., drugs with more intrasubject and intersubject variability).20 Hence, there are a number of issues that should be considered before a generic drug is substituted, and practitioners may want to prescribe a specific brand-name drug based on the pharmacologic profile of that drug and the specific way that the drug may affect a given patient.

What Constitutes a Drug: Development and Approval of Therapeutic Agents

In the United States, the Food and Drug Administration (FDA) is responsible for monitoring the use of existing drugs as well as developing and approving of new ones.9,19,21 The analogous body in Canada is the Health Products and Food Branch of the Department of National Health and Welfare. The two primary concerns of these agencies are (1) whether or not the drug is effective in treating a certain condition and (2) whether the drug is reasonably safe for human use.

Substitution of Generic Drugs for Brand-Name Products

A common question among practitioners and patients is whether the generic form of a drug can be substituted for the brand-name product. Generic forms are typically less expensive than their brand-name counterparts, and substitution of a generic drug can help reduce health care costs.16 The generic form of the drug should be as safe and effective as the original brand-name product, provided that the generic form satisfies certain criteria.10,29 Specifically, the generic form should undergo testing to establish that it has the same type and amount of the active ingredient(s), the same administration route, the same pharmacokinetic

Drug Approval Process

The development of a new drug involves extensive preclinical (animal) and clinical (human) studies.19,21 The basic procedure for testing a new drug is outlined here and is summarized in Table 12. Details about the phases of drug testing can also be found on the FDA website (

SECTION 1 General Principles of Pharmacology

Table 12
Testing Phase Preclinical testing


Purpose Initial laboratory tests to determine drug effects and safety Subjects Laboratory animals Usual Time Period 12 yrs

Investigational New Drug (IND) Application Human (clinical) testing: Phase I Determine effects, safe dosage, pharmacokinetics Assess drugs effectiveness in treating a specific disease/disorder Assess safety and effectiveness in a larger patient population Small number ( 100) of healthy volunteers Limited number (200300) patients with target disorder 1 yr

Phase II

2 yrs

Phase III

Large number (10003000) patients targeted

3 yrs

New Drug Application (NDA) Approval Phase IV (postmarketing surveillance) Monitor any problems that occur after NDA approval General patient population Indefinite

Animal (Preclinical) Studies

Drugs are typically tested in animals initially, often using several different species. Initial information on the basic pharmacokinetic and pharmacodynamic properties of the compound is obtained. Information on dosage and toxicity is also obtained from these animal trials.

Human (Clinical) Studies

If the results from animal trials are favorable, the drug sponsor files an investigational new drug (IND) application with the FDA. If approved as an IND, the sponsor may begin testing the drug in humans. Human, or clinical testing, is divided into three primary phases. Phase I. The drug is usually tested in a relatively small number of healthy volunteers. The purpose of this phase is to obtain some initial information about the pharmacologic actions, and the drugs possible toxic effects in humans. In general, between 20 to 80 subjects are studied in phase 1, but the actual number of subjects will vary according to the drug, Phase II. The drug is tested in a relatively small sample (200 to 300 people) with a specific dis-

ease or pathologic condition. The primary goal of phase 2 is to evaluate the effectiveness of the drug, and to assess the side effects and other risks. Phase III. Clinical evaluation is expanded to include more patients (several hundred to several thousand) as well as more evaluators. Additional information is obtained regarding the drugs safety and effectiveness in a large patient population. At the end of phase III, the drug sponsor applies for a new drug application (NDA). Results from clinical testing are reviewed extensively by the FDA, and if found favorable, the NDA is approved. At this point, the drug can be marketed and prescribed for use in the general population. A fourth phase known as postmarketing surveillance should be instituted after the NDA is approved. Postmarketing surveillance refers to all of the methods used to continue monitoring drug safety and effectiveness after approval for public use.19,21 These methods often consist of reports from health care providers that describe specific rare adverse effects that were not discovered during clinical testing.24 A certain drug, for example, could cause a specific adverse effect in only 1

Chapter 1 Basic Principles of Pharmacology

in 10,000 patients taking the drug.1 It is very likely that such an adverse effect could be missed during phase I through phase III of the clinical trials because the drug is typically tested only in a few thousand subjects (e.g., 1000 to 3000 people). In addition to monitoring adverse effects, postmarketing surveillance can use more formal research methods to obtain information about how a specific drug is used in clinical practice and how that drug compares to similar drugs on the market.24 Hence, postmarketing surveillance has been advocated as being critical in ensuring that the safety and efficacy of the drug continues to be monitored when it is used by the general patient population.18,24 The development of a new drug in the United States is an extremely expensive and time-consuming process.11 The time course for the entire testing process from the beginning of animal trials to the end of phase III human testing may be as long as 7 to 9 years. The FDA has made provisions, however, to shorten the development and review process for drugs designed to treat serious and life-threatening conditions, especially if the drug shows substantial benefits over existing treatments, or no drugs are currently available for these conditions.25 This type of accelerated development/review (also known as fast track drug development) is typically used for drugs that show promise in treating conditions such as cancer or acquired immunodeficiency syndrome (AIDS). Hence, these fast tract drugs may be made available for patient use even before formal clinical testing is completed.27 The FDA will, however, require that drug testing be continued even after the drug is approved, and efforts must be made to ensure that it actually provides the therapeutic benefits that were initially promised.27 The approval process can also be expedited if a drug has already received approval for treating one condition, but is now being considered for use in other supplemental conditions.24 The process of drug testing and approval does seem to be fairly rigorous in its ability to screen out ineffective or potentially harmful drugs. Out of thousands of newly synthesized compounds, only one will ever be released as a prescription drug.1

Prescription Versus Overthe-Counter Medication

In the United States, pharmacotherapeutic agents are divided into drugs requiring a prescription for use and drugs available as nonprescription, or over-thecounter (OTC).8 Nonprescription drugs can be pur-

chased directly by the consumer, whereas prescription medications may be ordered or dispensed only by an authorized practitioner (i.e., physician, dentist, or other appropriate health care provider). Prescription or nonprescription drug classification falls under the jurisdiction of the FDA.8 In general, OTC medications are used to treat relatively minor problems and to make the consumer more comfortable until the condition is resolved. These medications have been judged to be safe for use by the consumer without direct medical supervision, and the chances of toxic effects are usually small when the medications are taken in the recommended amounts.8 Of course, the patient may ingest more than the recommended amount, and in the case of an overdose, the danger always exists for potentially harmful effects, even if the drug is nonprescription in nature.6,15,22 The role of OTC products in the health care market has expanded dramatically in recent years.4,23 Many drugs that were formerly available only by prescription are now available in a nonprescription form. Transition of a prescription drug to an OTC product usually occurs when the drugs marketing company applies to the FDA and receives approval to develop and market it in a nonprescription form. FDA approval is based on the drug having an adequate safety profile, and the FDA may require other stipulations such as lowering the drug dosage in the OTC product. The fact that more and more prescription drugs are now available in a nonprescription form offers some obvious benefits. Increased availability of OTC products can make it easier for consumers to gain access to these medications.4,5 In addition, OTC products are typically less expensive than prescription drugs, and the purported savings might help contain overall medication costs. The actual cost to the patient, however, might be greater for an OTC product because the patient must pay directly out of pocket.4 That is, health care programs with prescription drug plans may cover the majority of a prescription drugs cost, whereas the patient often must pay directly for the entire cost of an OTC product. The actual money spent by patients (i.e., the out-of-pocket cost) might therefore be greater for OTC products compared to prescription drugs. Hence the overall benefits of OTC products on health care costs remains complex.4 Despite the potential benefits of OTC products, there are some obvious concerns about their increased use and emphasis on self-care that permeates todays health care market. Consumers must realize that these products are important therapeutic medications and

SECTION 1 General Principles of Pharmacology

must be used appropriately.23,26 There is also the chance that inappropriate OTC use can cause serious interactions with a patients prescription medications, or that OTC products can delay the use of more effective medications.4 The impact of such OTC compounds is discussed in this text in the appropriate chapters. It is therefore clear that consumers need to be educated about the use of such medications and reminded that OTC products can produce substantial benefits and adverse effects. All health care providers, including physical therapists and occupational therapists, need to be in a position to help educate and counsel their patients about the benefits and drawbacks of such medications. While therapists should not directly prescribe or administer OTC products, therapists can provide information about the proper use and potential benefits of these medications.

Controlled Substances
In 1970, federal legislation was enacted to help control the abuse of legal and illegal drugs. The Comprehensive Drug Abuse Prevention and Control Act (or Controlled Substances Act) placed drugs into specific categories, or schedules, according to their potential for abuse.12 Descriptions of the schedules for controlled drugs can be found on the FDA website (http://www.fda.goc/opacom/laws/cntrlsbb.htm), and these schedules are described briefly below. Schedule I. These drugs are regarded as having the highest potential for abuse, and are not typically used as an acceptable medical treatment in the United States. Legal use of agents in this category is restricted to approved research studies or therapeutic use in a very limited number of patients (e.g., use of marijuana as an antiemetic). Examples of schedule I drugs include heroin, lysergic acid diethylamide (LSD), psilocybin, mescaline, peyote, marijuana, tetrahydrocannabinols, and several other hallucinogens. Schedule II. Drugs in this category are approved for specific therapeutic purposes but still have a high potential for abuse and possible addiction. Examples include opioids such as morphine and fentanyl, and drugs containing methamphetamine. Schedule III. Although these drugs have a lower abuse potential than those in schedules I and II, there is still the possibility of developing mild to moderate physical dependence, strong

psychologic dependence, or both. Drugs in schedule III include certain opioids (e.g., codeine) that are combined in a limited dosage with other nonopioid drugs. Other drugs in this category are anabolic steroids, certain barbiturates, and amphetamines that are not included in schedule II. Schedule IV. These drugs supposedly have a lower potential for abuse than schedule III drugs, with only a limited possibility of physical dependence, psychologic dependence, or both. Examples include certain antianxiety drugs (meprobamate), certain barbiturates (barbital, phenobarbital), and a variety of other depressants and stimulants. Schedule V. These drugs have the lowest relative abuse potential. Drugs in this category consist primarily of low doses of opioids that are used in cough medications and antidiarrheal preparations. Several other criteria relate to the different controlled substance schedules, such as restrictions on prescription renewal and penalties for illegal possession of drugs in different schedules. For a further discussion of controlled substances, the reader is referred to another source.12

Basic Concepts in Drug Therapy

All drugs exert their beneficial effects by reaching some specific target cell or tissue. On the cellular level, the drug in some way changes the function of the cell either to help restore normal physiologic function or to prevent a disease process from occurring. In general, the dose of a drug must be large enough to allow an adequate concentration to reach the target site, thus producing a beneficial response. However, the administered dosage must not be so excessive that toxicologic effects are produced. Some aspects of the relationship between dose and response are discussed here.

Dose-Response Curves and Maximal Efficacy

The relationship between the dose of a drug and a specific response to the drug is illustrated in Figure 12. Typically, very low doses do not produce any observable effect. At some threshold dose, the response

Chapter 1 Basic Principles of Pharmacology

Ceiling effect


ence of the plateau associated with maximal efficacy can be used to indicate specific information about the binding of the drug to cellular receptors. The relevance of dose-response curves to drug-receptor interactions is discussed further in Chapter 4.

Threshold dose

Dose (log scale)

FIGURE 12 Dose-response curve.

begins to occur and continues to increase in magnitude before reaching a plateau. The plateau in the response indicates that there will be no further increment in the response even if the dosage continues to be increased. The point at which there is no further increase in the response is known as ceiling effect, or maximal efficacy, of the drug.24 Dose-response curves are used to provide information about the dosage range over which the drug is effective, as well as the peak response that can be expected from the drug. In addition, the characteristic shape of the dose-response curve and the pres-

One criterion used frequently when comparing drugs is the concept of potency. Potency is related to the dose that produces a given response in a specific amplitude.24 When two drugs are compared, the more potent drug requires a lower dose to produce the same effect as a higher dose of the second drug. For instance, in Figure 13, a dose of 10 mg of drug A would lower blood pressure by 25 percent, whereas 80 mg of drug B would be required to produce the same response. Consequently, drug A would be described as being more potent. It should be noted that potency is not synonymous with maximal efficacy. Drug B is clearly able to exert a greater maximal effect than drug A. Consequently, the term potency is often taken to be much more significant than it really is.24 The potency of a drug is often misinterpreted by the layperson as an indication of the drugs overall therapeutic benefits, whereas potency really just refers to the fact that less of the compound is required to produce a given response. In fact, neither potency nor maximal efficacy fully indicates a drugs therapeutic
Drug "B"

Decrease in Mean Arterial Pressure


Drug "A"




40 Dose (mg)



FIGURE 13 Relative potency and maximal efficacy of two drugs. Drug A is more potent, and drug B has a greater maximal efficacy.


SECTION 1 General Principles of Pharmacology

potential. Other factors such as the therapeutic index (described further on) and drug selectivity (see Chapter 4) are also important in comparing and ultimately choosing the best medication for a given problem.

Elements of Drug Safety

Quantal Dose-Response Curves and the Median Effective Dose
The dose-response curves shown in Figures 12 and 13 represent the graded response to a drug as it would occur in a single individual or in a homogeneous population. In reality, variations in drug responses that are caused by individual differences in the clinical population need to be considered when trying to assess whether a drug is safe as well as effective. Consequently, the relationship between the dose of the drug and the occurrence of a certain response is measured in a large group of people (or animals if the drug is being tested preclinically). When plotted, this relationship yields a cumulative, or quantal, dose-response curve (Fig. 14).24 This curve differs from the dose-response curve discussed previously in that it is not the magnitude of the response that increases with increasing the dosage, but the percentage of the population who

exhibit a specific response as the dosage is increased. The response is not graded; it is either present or it is absent in each member of the population. For example, a headache medication is administered in an increasing dosage to 1000 people. At some dose, some of the individuals will begin to respond to the drug by reporting the absence of their headache. As the dosage is increased, more and more individuals will experience pain relief because of the medication, until finally 100 percent of the population report that their headaches are gone. Again, it is the percentage of the population who respond in a specific way (e.g., reporting loss of their headaches) that is measured relative to the dose of the drug. An important reference point in this type of cumulative dose-response curve is the median effective dose (ED50).24 This is the dose at which 50 percent of the population respond to the drug in a specified manner.

Median Toxic Dose

In the aforementioned example, relief from pain was the desired response, which is often termed the beneficial effect. As dosages of the drug continue to be increased, however, adverse or toxic effects may become apparent. To continue the earlier example, higher doses of the same medication may be associated

Percent of Individuals Responding

"Beneficial" Effect 100

Toxic Effect


0 5 10 ED50 20 40 80 160 320 TD50 640 1280

Dose (mg)
FIGURE 14 Cumulative dose-response curve. The median effective dose (ED50) is 10 mg, and the median toxic dose (TD50) is 320 mg. The therapeutic index (TI) for this drug is 32.

Chapter 1 Basic Principles of Pharmacology


with the appearance of a specific toxic effect such as acute gastric hemorrhage. As the dosage is increased, more and more individuals will then begin to exhibit that particular adverse effect. The dose at which 50 percent of the group exhibits the adverse effect is termed the median toxic dose (TD50). In animal studies, the toxic effect studied is often the death of the animal. In these cases, high doses of the drug are used to determine the median lethal dose (LD50)the dose that causes death in 50 percent of the animals studied.24 Of course, the LD50 is not a relevant term in clinical use of the drug in humans, but it does serve to provide some indication of the drugs safety in preclinical animal trials.

Therapeutic Index
The median effective and toxic doses are used to determine the therapeutic index (TI).24 The TI is calculated as the ratio of the TD50 to the ED50: TI TD50 ED50

has a TI of 8, and the sedative-hypnotic diazepam (Valium) has a TI equal to 3. Other prescription agents such as cancer chemotherapeutics (methotrexate, vincristine, and so on) may have very low TIs, some close to 1. However, a low TI is often acceptable in these agents, considering the critical nature of cancer and similar serious conditions. The consequences of not using the drug outweighs the risks of some of the toxic effects. To help keep the risk of toxicity to a minimum with low-TI drugs, it is generally advisable to periodically monitor blood levels. This helps prevent concentrations from quickly reaching toxic levels. This precaution is usually not necessary with high-TI drugs, because there is a greater margin of error (i.e., blood levels can rise quite a lot above the therapeutic concentration before becoming dangerous).

In its broadest sense, pharmacology is the study of the effects of chemicals on living organisms. Most discussions of clinical pharmacology deal primarily with the beneficial effects of specific drugs on humans, and the manner in which these drugs exert their therapeutic effects. Since all drugs have the potential to produce unwanted or toxic responses, some discussion of a drugs adverse effects is also essential in pharmacology. Drugs used therapeutically are subjected to extensive testing prior to approval for use in humans and are classified as either prescription or over-the-counter, depending on their dosage, effectiveness, and safety profile. Finally, certain characteristic relationships exist between the dose of a drug and the response or effect it produces. Such relationships can provide useful information about drug efficacy and potency and about the relative safety of different compounds.

In animal studies in which the median lethal dose is known, the TI is often calculated using the LD50 in place of the TD50. In either human or animal studies, the TI is used as an indicator of the drugs safety.24 The greater the value of the TI, the safer the drug is considered to be. In essence, a large TI indicates that it takes a much larger dose to evoke a toxic response than it does to cause a beneficial effect. It should be noted, however, that the TI is a relative term. Acetaminophen, a nonprescription analgesic, has a TI of approximately 27 (i.e., the ratio of the median toxic dose to the median effective dose equals 27). Prescription agents tend to have lower TIs. For instance, the narcotic analgesic meperidine (Demerol)

1. Berkowitz BA. Basic and clinical evaluation of new drugs. In: Katzung BG, ed. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw Hill; 2004. 2. Berman A. Reducing medication errors through naming, labeling, and packaging. J Med Syst. 2004; 28:929. 3. Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003;25:15781592. 4. Brass EP. Changing the status of drugs from prescription to over-the-counter availability. N Engl J Med. 2001;345:810816.

5. Brass EP. Implications of a switch from prescription to over-the-counter status for allergy drugs. Curr Allergy Asthma Rep. 2004;4:245250. 6. Bromer MQ, Black M. Acetaminophen hepatotoxicity. Clin Liver Dis. 2003;7:351367. 7. Chen ML, Shah V, Patnaik R, et al. Bioavailability and bioequivalence: an FDA regulatory overview. Pharm Res. 2001;18:16451650. 8. Corelli RL. Therapeutic and toxic potential of overthe-counter agents. In: Katzung BG, ed. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw Hill; 2004. 9. Cowan CC. The process of evaluating and regulating a new drug: phases of a drug study. AANA J. 2002;70: 385390.


SECTION 1 General Principles of Pharmacology 20. Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther. 2003; 25:28752890. 21. Moore SW. An overview of drug development in the United States and current challenges. South Med J. 2003;96:12441256. 22. Motola G, Mazzeo F, Rinaldi B, et al. Self-prescribed laxative use: a drug-utilization review. Adv Ther. 2002; 19:203238. 23. Newton GD, Pray WS, Popovich NG. New OTC drugs and devices 2003: a selective review. J Am Pharm Assoc (Wash DC). 2004;44:211225. 24. Nies AS. Principles of therapeutics. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001. 25. Reichert JM. Trends in development and approval times for new therapeutics in the United States. Nat Rev Drug Discov. 2003;2:695702. 26. Roumie CL, Griffin MR0. Over-the-counter analgesics in older adults: a call for improved labelling and consumer education. Drugs Aging. 2004;21:485498. 27. Shih WJ, Ouyang P, Quan H, Lin Y, Michiels B, Bijnens L. Controlling type I error rate for fast track drug development programmes. Stat Med. 2003;22: 665675. 28. Venes D, Thomas CL (eds). Tabers Cyclopedic Medical Dictionary. 19th ed. Philadelphia: FA Davis;2004. 29. Welage LS, Kirking DM, Ascione FJ, Gaither CA. Understanding the scientific issues embedded in the generic drug approval process. J Am Pharm Assoc (Wash DC). 2001;41:856867.

10. Dighe SV. A review of the safety of generic drugs. Transplant Proc. 1999;31(suppl 3A):23S24S. 11. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003;22:151185. 12. Edwards L. Appendix I. Principles of prescription order writing and patient compliance. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001. 13. Gremillion L, Hogan DJ. Dermatologic look- or sound-alike medications. J Drugs Dermatol. 2004;3: 6164. 14. Hoffman JM, Proulx SM. Medication errors caused by confusion of drug names. Drug Saf. 2003;26: 445452. 15. Jones A. Over-the-counter analgesics: a toxicology perspective. Am J Ther. 2002;9:245257. 16. Kirking DM, Ascione FJ, Gaither CA, Welage LS. Economics and structure of the generic pharmaceutical industry. J Am Pharm Assoc. 2001;41: 578584. 17. Lambert BL, Chang KY, Lin SJ. Immediate free recall of drug names: effects of similarity and availability. Am J Health Syst Pharm. 2003;60:156168. 18. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287:22152120. 19. Lipsky MS, Sharp LK. From idea to market: the drug approval process. J Am Board Fam Pract. 2001;14: 362367.


Pharmacokinetics I: Drug Administration, Absorption, and Distribution

Pharmacokinetics is the study of the way that the body deals with pharmacologic compounds. In other words, what does the body do to the drug? This includes the manner in which the drug is administered, absorbed, distributed, and eventually eliminated from the body. These topics are discussed in this chapter and the next. system in a fairly controlled manner. This avoids the large, sudden increase in plasma drug levels, which can occur when the drug is administered by other methods such as through intravenous injection. Most medications that are administered orally are absorbed from the small intestine, thus utilizing the large surface area of the intestinal microvilli to enhance its entry into the body. Several disadvantages may preclude drugs from being given orally. Drugs that are administered by mouth must have a relatively high degree of lipid solubility in order to pass through the gastrointestinal mucosa and into the bloodstream. Large, nonlipidsoluble compounds are absorbed very poorly from the alimentary canal and will eventually be lost from the body in the feces. Absorption of some nonlipid-soluble substances (peptides, small proteins) can be enhanced to some extent by encapsulating these agents in lipid vesicles (liposomes); this technique was recently developed to enable the oral administration of drugs that were formerly administered only through injection or some other parenteral route.82 Other drawbacks to the oral route include the fact that certain medications may irritate the stomach and cause discomfort, vomiting, or even damage to the gastric mucosa. The acidic environment and presence of digestive proteases in the stomach may also cause various compounds to be degraded and destroyed prior to absorption from the gastrointestinal tract.49 Drugs that are given orally are subject to a phenomenon known as the first-pass effect.10,86 After

Routes of Administration
In general, drugs can be administered via two primary routes: through the alimentary canal (enteral administration) or through nonalimentary routes (parenteral administration). Each major route has several variations, and each offers distinct advantages and disadvantages. The primary features of some of the major routes are discussed here. For a more detailed description of the specific methodology involved in drug administration, the reader is referred to several excellent discussions of this topic.10,34,86

The primary way that drugs are given enterally is through the oral route. This is the most common method of administering medications and offers several distinct advantages. Oral administration is the easiest method of taking medications, especially when self-administration is necessary or desired. The oral route is also relatively safe because drugs enter the


SECTION 1 General Principles of Pharmacology

Table 21
Route Enteral Oral


Advantages Easy, safe, convenient Disadvantages Limited or erratic absorption of some drugs; chance of firstpass inactivation in liver Drug must be easily absorbed from oral mucosa Poor or incomplete absorption; chance of rectal irritation Examples Analgesics; sedativehypnotics; many others


Rapid onset; not subject to firstpass inactivation Alternative to oral route; local effect on rectal tissues



Laxatives; suppository forms of other drugs

Parenteral Inhalation Rapid onset; direct application for respiratory disorders; large surface area for systemic absorption Provides more direct administration to target tissues; rapid onset Local effects on surface of skin Chance of tissue irritation; patient compliance sometimes a problem General anesthetics; antiasthmatic agents


Chance of infection if sterility is not maintained

Insulin; antibiotics; anticancer drugs; narcotic analgesics Antibiotic ointments; creams used to treat minor skin irritation and injury Nitroglycerin; motion sickness medications; drugs used with phonophoresis and iontophoresis


Only effective in treating outer layers of skin


Introduces drug into body without breaking the skin; can provide steady, prolonged delivery via medicated patch

Drug must be able to pass through dermal layers intact

absorption from the alimentary canal, the drug is transported directly into the liver via the portal vein, where a significant amount of the drug may be metabolized and destroyed prior to reaching its site of action. The dosage of the orally administered drug must be sufficient enough to allow an adequate amount of the compound to survive hepatic degradation and to eventually reach the target tissue.10 Some drugssuch as nitroglycerinundergo such extensive inactivation from the first-pass effect that it is usually preferable to administer them through nonoral routes.86 A final limitation of the oral route is that the amount and rate at which the drug eventually reaches the bloodstream tends to be somewhat less predictable with oral administration compared with more direct routes, such as injection. Factors that affect intestinal absorption (intestinal infection, presence of food,

rate of gastric emptying, amount of visceral blood flow, and so on) can alter the usual manner in which a drug is absorbed into the body from the gastrointestinal tract.6,21,39,86

Sublingual and Buccal

Drugs are administered sublingually by placing the drug under the tongue. Buccal administration occurs when the drug is placed between the cheek and gums. A drug that is administered sublingually or buccally is then absorbed through the oral mucosa into the venous system that is draining the mouth region. These veins eventually carry blood to the superior vena cava, which in turn carries blood to the heart. Consequently, a drug administered sublingually or buccally can reach the systemic circulation without being sub-

Chapter 2 Pharmacokinetics I


jected to first-pass inactivation in the liver.70,90 This provides an obvious advantage for drugs such as nitroglycerin that would be destroyed in the liver when absorbed from the stomach or intestines. These routes also offer a means of enteral administration to people who have difficulty swallowing or to patients who cannot be given drugs rectally.54 The restrictions of the sublingual and buccal routes are that the amount of drug that can be administered is somewhat limited, and the drug must be able to pass easily through the oral mucosa in order to reach the venous drainage of the mouth.

A final method of enteral administration is via the rectum. Many drugs are available as rectal suppositories to allow administration through this route. This method is less favorable because many drugs are absorbed poorly or incompletely, and irritation of the rectal mucosa may occur.86 Rectal administration does offer the advantage of allowing drugs to be given to a patient who is unconscious, or when vomiting prevents drugs from being taken orally. However, the rectal route is used most often for treating local conditions such as hemorrhoids.

to the bronchial and alveolar tissues for the treatment of specific pulmonary pathologies.42 The pulmonary route may also be a potential way to administer larger nonlipid-soluble agents such as peptides, small proteins (including insulin), and DNA.3,30,69 One limitation of the inhalation route is that the drug must not irritate the alveoli or other areas of the respiratory tract. Also, some patients have trouble administering drugs by this route, and drug particles tend to be trapped by cilia and mucus in the respiratory tract. Both of these factors tend to limit the ability to predict exactly how much of the drug eventually reaches the lungs. Efforts continue to advance the use of inhaled drugs by improving the physicochemical properties of these drugs, and also by improving the devices used to deliver these drugs (i.e., inhalers).20 Technological advancements in inhaled drugs will be addressed in more detail when respiratory medications are addressed later in this text (see Chapter 26).

Various types of injection can be used to introduce the drug either systemically or locally. If sterility is not maintained, all types of injection have the disadvantage of possible infection, and certain types of injection are more difficult, if not impossible, for the patient to self-administer. Specific types of injection include the following routes. Intravenous. The bolus injection of a medication into a peripheral vein allows an accurate, known quantity of the drug to be introduced into the bloodstream over a short period of time, frequently resulting in peak levels of the drug appearing almost instantaneously in the peripheral circulation and thus reaching the target site rapidly. This occurrence is advantageous in emergency situations when it is necessary for the medication to exert an immediate effect. Of course, adverse reactions may also occur because of the sudden appearance of large titers of the drug in the plasma. Any unexpected side effects or miscalculations in the amount of the administered drug are often difficult to deal with after the full dose has been injected. In certain situations, an indwelling intravenous cannula (IV line) can be used to allow the prolonged, steady infusion of a drug into the venous system. This method prevents large fluctuations in the plasma concentration of the drug and allows the dosage of drug to be maintained at a specific level for as long as desired. Intra-arterial. The injection of a drug directly into an artery is understandably a difficult and dangerous

All methods of drug administration that do not use the gastrointestinal tract are termed parenteral. Parenteral administration generally allows the drug to be delivered to the target site more directly, and the quantity of the drug that actually reaches the target site is often more predictable.86 Also, drugs given parenterally are not usually subject to first-pass inactivation in the liver. Other advantages and disadvantages of various parenteral routes are discussed further on in this section.

Drugs that exist in a gaseous or volatile state, or that can be suspended as tiny droplets in an aerosol form, may be given via inhalation. Pulmonary administration is advantageous because of the large (alveolar) surface area for diffusion of the drug into the pulmonary circulation and it is generally associated with rapid entry of the drug into the bloodstream.43 This method is used extensively in administering the volatile general anesthetics (e.g., halothane) and it is also advantageous when applying medications directly


SECTION 1 General Principles of Pharmacology

procedure. This method permits a large dose of the medication to reach a given site, such as a specific organ, and may be used to focus the administration of drugs into certain tissues. Intra-arterial injections are used occasionally in cancer chemotherapy to administer the anticancer drug directly to the tumor site with minimal exposure of the drug to other healthy tissues. This route may also be used to focus the administration of other substances such as radiopaque dyes for various diagnostic procedures. Subcutaneous. Injecting medications directly beneath the skin is used when a local response is desired, such as in certain situations requiring local anesthesia. Also, a slower, more prolonged release of the medication into the systemic circulation can be achieved in situations where this is the desired effect. A primary example is insulin injection in a patient with diabetes mellitus. Subcutaneous administration provides a relatively easy route of parenteral injection that can be performed by patients themselves, providing they are properly trained. Some limitations are that the amount of drug that can be injected in this fashion is fairly small and that the injected drug must not irritate or inflame the subcutaneous tissues. The subcutaneous route can also be used when certain types of drug preparations are implanted surgically beneath the skin, so that the drug is slowly dispersed from the implanted preparation and then absorbed into the bloodstream for prolonged periods of time.62,86 A common example of this form of subcutaneous administration is the use of implanted hormonal contraceptive products (e.g., Norplant).9,53 The use of these implantable contraceptives is discussed in more detail in Chapter 30. Intramuscular. The large quantity of skeletal muscle in the body allows this route to be an easily accessible site for parenteral administration. Intramuscular injections can be used to treat a problem located directly in the injected muscle. For example, botulinum toxin and other substances can be injected directly into hyperexcitable muscles to control certain types of muscle spasms or spasticity (see Chapter 13).7,78 Alternatively, intramuscular injection can be used as a method for a relatively steady, prolonged release of the drug into the systemic circulation to control conditions such as psychosis,2 or to administer certain vaccines. Intramuscular injection offers the advantage of providing a relatively rapid effect (i.e., within a few minutes), while avoiding the sudden, large increase in plasma levels seen with intravenous injection. The

major problem with intramuscular administration is that many drugs injected directly into a muscle cause significant amounts of local pain and prolonged soreness, tending to limit the use of this route for repeated injections. Intrathecal. Intrathecal injections are given by injecting the medication within a sheath, and frequently refer to injections within the spinal subarachnoid space (i.e., the space between the arachnoid membrane and the pia mater that help form the meninges surrounding the spinal cord). This particular type of intrathecal route allows drugs such as narcotic analgesics, local anesthetics, and antispasticity drugs to be applied directly to an area adjacent to the spinal cord, thereby allowing these drugs to gain better access to the cord.55,60,79 Also, intrathecal injections allow certain drugssuch as antibiotics and anticancer drugsto bypass the blood-brain barrier and reach the central nervous system (see Chapter 5).86 Other intrathecal injections include administration of the drug within a tendon sheath or bursa, which may be used to treat a local condition such as an inflammation within those structures.

Drugs given topically are applied to the surface of the skin or mucous membranes. Most medications applied directly to the skin are absorbed fairly poorly through the epidermis and into the systemic circulation and are used primarily to treat problems that exist on the skin itself. Common examples of topical administration include the use of antibiotics to treat cutaneous infections, application of anti-inflammatory steroids to reduce skin inflammation, and the use of various topical products to promote wound healing.11,59,74,85 Topical application to mucous membranes is also used frequently to treat problems on the membrane itself.86 Significant amounts of the drug, however, can be readily absorbed through the mucous membrane and into the bloodstream. Topical application of drugs to mucous membranes can therefore provide a fairly easy and convenient way to administer drugs systemically. Certain medications, for example, can be administered to the nasal mucosa (via nasal spray),22,36 to the occular membranes (via eye drops),87 or to other mucous membranes to facilitate systemic absorption and treat disorders throughout the body.86 Nonetheless, the potential for adverse systemic effects must also be considered if large amounts of topically administered drugs are absorbed inadvertently into the body.86

Chapter 2 Pharmacokinetics I


Unlike topical administration, transdermal application consists of applying drugs directly to the surface of the skin with the intent that they will be absorbed through the dermal layers and into either the subcutaneous tissues or the peripheral circulation. A transdermally administered drug must possess two basic properties: (1) it must be able to penetrate the skin, and (2) it must not be degraded to any major extent by drug-metabolizing enzymes located in the dermis.44 Absorption may be enhanced by mixing the drug in an oily base or in some other chemical enhancer, thus increasing solubility and permeability through the dermis.4,80 Transdermal administration provides a slow, controlled release of the drug into the body that is effective in maintaining plasma levels of the drug at a relatively constant level for prolonged periods of time.65 Drugs that can be administered transdermally are often delivered through medicated patches that can be adhered to the skin much like a small adhesive bandage. This method has been used for some time to allow the prolonged administration of drugs such as nitroglycerin and some antimotion sickness medications such as scopolamine. The use of transdermal patches has been expanded recently to include other medications such as hormonal agents (estrogen, testosterone) and opioid analgesics (fentanyl).58 Likewise, transdermal nicotine patches have received a great deal of attention for their use in helping people to quit smoking cigarettes.58 Researchers continue to explore the use of the transdermal route, and the use of transdermal patches continues to gain acceptance as a safe and effective method of administering many medications. The transdermal route also includes the use of iontophoresis and phonophoresis to administer the drug. In iontophoresis, electric current is used to drive the ionized form of the medication through the skin.4,18,19,56 Phonophoresis uses ultrasound waves to enhance transmission of the medication through the dermis.4,12,56 Both phonophoresis and iontophoresis are often used to treat pain and inflammation by transmitting specific medications to a subcutaneous tissue such as a muscle, tendon, or bursa. These forms of transdermal administration are important in a rehabilitation setting since they are often administered by a physical therapist following a prescription written by a physician. Specific medications that can be administered via iontophoresis or phonophoresis are listed in Appendix A. For a more detailed description of how

these transdermal routes are employed, the reader is referred to several additional sources.12,18,19

Drug Absorption and Distribution: Bioavailability

Although several routes exist for the administration of drugs, merely introducing the drug into the body does not ensure that the compound will reach all tissues uniformly or that the drug will even reach the appropriate target site. For instance, oral administration of a drug that affects the myocardium will not have any pharmacologic effect unless the drug is absorbed from the gastrointestinal tract into the bloodstream. The extent to which the drug reaches the systemic circulation is referred to as bioavailability, which is a parameter expressed as the percentage of the drug administered that reaches the bloodstream.17,86 For instance, if 100 g of a drug is given orally, and 50 g eventually make it into the systemic circulation, the drug is said to be 50 percent bioavailable. If 100 g of the same compound were injected intravenously, the drug would be 100 percent bioavailable by that route. Consequently, bioavailability depends on the route of administration as well as the drugs ability to cross membrane barriers. Once in the systemic circulation, further distribution into peripheral tissues may also be important in allowing the drug to reach the target site. Many drugs must eventually leave the systemic capillaries and enter other cells. Thus, drugs have to move across cell membranes and tissue barriers to get into the body and be distributed within the body. In this section, the ability of these membranes to affect absorption and distribution of drugs is discussed.

Membrane Structure and Function

Throughout the body, biologic membranes act as barriers that permit some substances to pass freely, while others pass through with difficulty or not at all. This differential separation serves an obvious protective effect by not allowing certain substances to enter the body or by limiting the distribution of the substance within the body. In effect, the body is separated into various compartments by these membranes. In the case of pharmacotherapeutics, there is often the need for the drug to cross one or more of these membrane barriers to reach the target site. The ability of the membrane to act as a selective barrier is related to the membranes normal structure


SECTION 1 General Principles of Pharmacology

and physiologic function. The cell membrane is composed primarily of lipids and proteins. Membrane lipids are actually phospholipids, which are composed of a polar, hydrophilic head (which contains a phosphate group) and a lipid, hydrophobic tail (Fig. 21). The phospholipids appear to be arranged in a bilayer, with the hydrophobic tails of the molecule oriented toward the membranes center and the hydrophilic heads facing away from the center of the membrane. Interspersed throughout the lipid bilayer are membrane proteins, which can exist primarily in the outer or inner portion of the membrane or can span the entire width of the cell membrane (see Fig. 21). Recent evidence also suggests that the distribution of phospholipids and proteins within the cell membrane is not random, but that certain areas of the cell membrane are organized into special regions or domains.35,52,63 In particular, certain domains appear to consist primarily of lipids such as cholesterol and sphingolipids.27,50 These lipid domains are often described as lipid rafts that move freely about the cell membrane and these lipid rafts appear to be important in controlling various cell functions including cell signaling, endocytosis, and ion channel function.27,50 Future research will help further define the role of the lipid rafts and other specific domains within the cell membrane. The lipid bilayer that composes the basic structure of the cell membrane acts as a water barrier. The lipid portion of the membrane is essentially impermeable to water and other nonlipid-soluble substances (electrolytes, glucose). Lipid-soluble compounds (including most drugs) are able to pass directly through the membrane by becoming dissolved in the lipid

bilayer. Nonlipid-soluble substances, including water, may be able to pass through the membrane because of the presence of membrane pores.5 Small holes or channels appear to exist in the membrane, thereby allowing certain substances to pass from one side of the membrane to the other. These channels are believed to be formed by some of the membrane proteins that span the width of the membrane.41 The ability a substance has to pass through a specific pore depends primarily on the size, shape, and electrical charge of the molecule. Also, in excitable membranes (nerve, muscle) some of these pores are dynamic in nature and appear to have the ability to open and close, thus regulating the flow of certain ions in and out of the cell.73,91 These dynamic ion channels are especially important in pharmacology because many drugs can affect their ability to open and close, thus altering cell excitability by regulating the movement of ions across the cell membrane.45,81,84

Movement Across Membrane Barriers

Drugs and other substances that pass through biologic membranes usually do so via passive diffusion, active transport, facilitated diffusion, or some special process such as endocytosis (Fig. 22). Each of these mechanisms is discussed here.

Passive Diffusion
Drugs and other substances will pass through a membrane by way of diffusion providing two essential criteria are met. First, there must be some type of difference or gradient on one side of the membrane

(Singer SJ, Nicolson GJ. The fluid mosaic model of the structure of cell membranes. Science. 1972;175:720731.)

lipid bilayer

membrane phospholipids: hydrophilic "heads" hydrophobic "tails" membrane proteins

FIGURE 21 Schematic diagram of the cell membrane.

Chapter 2 Pharmacokinetics I
Passive Diffusion Active Transport Facilitated Diffusion Endocytosis


ATP ADP-Pi FIGURE 22 Schematic diagram summarizing the ways in which substances may cross the cell membrane. Energy is expended during active transport by hydrolyzing adenosine triphosphate (ATP) into adenosine diphosphate (ADP) and inorganic phosphate (Pi). The three other mechanisms do not require any net energy expenditure. See text for further discussion of how and when each mechanism is utilized.

compared to the other. A concentration gradient, for example, occurs when the concentration of the substance differs on one side of the membrane compared to that on the other side. When this gradient occurs, the diffusing substance can move downhill from the area of high concentration to that of low concentration. In addition to a concentration difference, diffusion can also occur because of the presence of a pressure gradient or, in the case of charged particles, an electrical potential gradient. The rate of the diffusion is dependent on several factors, including the magnitude of the gradient, the size of the diffusing substance, the distance over which diffusion occurs, and the temperature at which diffusion occurs.41 The term passive diffusion is often used to emphasize the fact that this movement occurs without expending any energy. The driving forces in passive diffusion are the electrical, chemical, and pressure differences on the two sides of the membrane. For passive diffusion through a membrane to occur, the second essential factor is that the membrane must be permeable to the diffusing substance. As mentioned earlier, nonlipid-soluble compounds can diffuse through the membrane via specific pores. Some nonlipid-soluble drugs such as lithium are small enough to diffuse through these pores. Many drugs, however, are able to diffuse directly through the lipid bilayer; hence, they must be fairly lipid soluble. Passive lipid diffusion is nonselective, and a drug with a high degree of lipid solubility can gain access to many tissues because of its ability to pass directly through the lipid portion of the cell membrane. As indicated earlier, certain nonlipidsoluble substancesincluding some proteinscan be encapsulated in lipid vesicles, thereby enhancing their lipid solubility and increasing their ability to cross lipid membranes by passive diffusion. Effect of Ionization on Lipid Diffusion. Passive lipid diffusion of certain drugs is also dependent on whether or not the drug is ionized. Drugs will diffuse more readily through the lipid layer if they are in their

neutral, nonionized form. Most drugs are weak acids or weak bases,86 meaning that they have the potential to become positively charged or negatively charged, depending on the pH of certain body fluids. In the plasma and in most other fluids, most drugs remain in their neutral, nonionized form because of the relatively neutral pH of these fluids. In specific fluids, however, a drug may exist in an ionized state, and the absorption of the drug will be affected because of the decreased lipid solubility associated with ionization. For instance, when a weak acid is in an acidic environment (e.g., gastric secretions of the stomach), it tends to be in its neutral, nonionized form. The same drug will become positively charged if the pH of the solution increases and becomes more basic (e.g., the digestive fluids in the duodenum). A weak acid such as aspirin will be nonionized and will therefore be absorbed fairly easily from the stomach because of its lipid solubility (Fig. 23). This same drug will be poorly absorbed if it reaches the basic pH of the duodenum and becomes ionized. Conversely, a drug that is a weak base will be ionized and poorly absorbed from the acidic environment of the stomach. The same drug will be nonionized and will therefore be lipid soluble when it reaches the duodenum, allowing it to be absorbed from the proximal small intestine. Diffusion Trapping. Changes in lipid solubility caused by ionization can also be important when the body attempts to excrete a drug in the urine. Here the situation becomes slightly more complex because the urine can sometimes be acidic and at other times basic in nature. In either situation, it is often desirable for the drug to remain ionized while in the urine so that the drug will be excreted from the body. If the drug becomes nonionized while in the nephron, it may be reabsorbed back into the body because of its increased lipid solubility. An ionized form of the drug will remain trapped in the nephron and will eventually be excreted in the urine.66 Thus, if the urine is basic, weak acids will become trapped in the nephron

(From Clark JB, Queener SF, and Karb VB. Pharmacological Basis of Nursing Practice 4th ed. St. Louis, MO: CV Mosby; 1993:p. 8, with permission.)

SECTION 1 General Principles of Pharmacology

pH 1 to 3

Weak acids

Weak bases

pH 5 to 7 Weak bases

Osmosis. Osmosis refers to the special case of diffusion where the diffusing substance is water. In this situation, water moves from an area where it is highly concentrated to an area of low concentration. Of course, permeability is still a factor when osmosis occurs across a membrane or tissue barrier. During osmosis, certain drugs may simply travel with the diffusing water, thus crossing the membrane by the process of bulk flow. This is usually limited to osmosis through the gaps between adjacent cells because membrane pores are often too small to allow the passage of the drug molecule along with the diffusing water.

Active Transport
pH 7 to 8


Active or carrier-mediated transport involves using membrane proteins to transport substances across the cell membrane (see Fig. 22). Membrane proteins that span the entire membrane may serve as some sort of carrier that shuttles substances from one side of the membrane to the other.41 Characteristics of active transport include the following: Carrier specificity. The protein carrier exhibits some degree of specificity for certain substances, usually discriminating among different compounds according to their shape and electrical charge. This specificity is not absolute, and some compounds that resemble one another will be transported by the same group of carriers. Expenditure of energy. The term active transport implies that some energy must be used to fuel the carrier system. This energy is usually in the form of adenosine triphosphate (ATP) hydrolysis. Ability to transport substances against a concentration gradient. Carrier-mediated active transport may be able to carry substances uphillthat is, from areas of low concentration to areas of high concentration. The role of active transport in moving drugs across cell membranes has some important implications. Essentially, the drug can use one of the bodys active transport systems if the drug resembles some endogenous substance that is routinely carried by the transport system. Thus, drugs that resemble amino acids and small peptides can be absorbed from the gastrointestinal (GI) tract via active transport proteins that normally absorb these substances into the body. Active transport systems in the kidneys, liver, brain, intestines, and placenta are likewise responsible for the movement of organic ions, peptides, and other

FIGURE 23 Effect of pH and ionization on absorption of drugs from the gastrointestinal tract. Weak acids and bases are absorbed from the stomach and duodenum, respectively, when they are in their neutral, nonionized form.

and will be excreted more readily. Weak bases will be excreted better if the urine is acidic. The importance of the kidneys in excreting drugs from the body is discussed further in Chapter 3. Diffusion Between Cell Junctions. So far, the diffusion of drugs and other substances through individual cell membranes has been discussed. Often, groups of cells will join together to form a barrier that separates one body compartment from another. In some locations, cells form tight junctions with each other and do not allow any appreciable space to exist between adjacent cells. In these cases, the primary way that a drug may diffuse across the barrier is by diffusing first into and then out of the other side of the cells comprising the barrier. Such locations include the epithelial lining of the gastrointestinal tract and the capillary endothelium of the brain (one of the reasons for the blood-brain barrier). In other tissues such as peripheral capillaries, there may be relatively large gaps between adjacent cells. Here, relatively large substances with molecular weights as high as 30,000 may be able to diffuse across the barrier by diffusing between adjacent cells.

Chapter 2 Pharmacokinetics I


substances across cell membranes, and these transport systems play an important role in the disposition of certain drugs within these tissues.23,40,83,89 Conversely, some drugs may exert their effect by either facilitating or inhibiting endogenous transport systems that affect cellular homeostasis. For example, some of the drugs used to treat excess gastric acid secretion (e.g., famotidine, ranitidine; see Chapter 27) inhibit the active transport of hydrogen ions into the stomach, thus reducing the formation of hydrochloric acid within the stomach.67 Hence, medications can interact with the bodys active transport systems in several ways and researchers continue to develop new methods to enhance a drugs effects by using or modifying active transport pathways.

Facilitated Diffusion
Facilitated diffusion, as the name implies, bears some features of both active transport and passive diffusion. A protein carrier is present in facilitated diffusion, but no net energy is expended in transporting the substance across the cell membrane.41 As a result, in most cases of facilitated diffusion there is an inability to transport substances uphill against a concentration gradient. The entry of glucose into skeletal muscle cells via facilitated diffusion is probably the best example of this type of transport in the body.61 As in active transport, the movement of drugs across membranes through facilitated diffusion is fairly infrequent, but certain medications may affect the rate at which endogenous facilitated diffusion occurs.

Special Processes
Certain cells have the ability to transport substances across their membranes through processes such as endocytosis. Here the drug is engulfed by the cell via an invagination of the cell membrane. Although limited in scope, this method does allow certain large, nonlipid-soluble drugs to enter the cell.

Distribution of Drugs Within the Body

Factors Affecting Distribution
Following administration, the extent to which a drug is uniformly distributed throughout the body or sequestered in a specific body compartment depends on several factors:

1. Tissue permeability. As discussed earlier, the ability to pass through membranes radically affects the extent to which a drug moves around within the body. A highly lipid-soluble drug can potentially reach all of the different body compartments and enter virtually every cell it reaches.88 A large nonlipid-soluble compound will remain primarily in the compartment or tissue to which it is administered. Also, certain tissues such as the brain capillary endothelium have special characteristics that limit the passage of drugs. This so-called blood-brain barrier limits the movement of drugs out of the bloodstream and into the central nervous system tissue. 2. Blood flow. If a drug is circulating in the bloodstream, it will gain greater access to tissues that are highly perfused. More of the drug will reach organs that receive a great deal of blood flow such as the brain, kidneys, and exercising skeletal musclethan will other, less active tissues such as adipose stores.86 Similarly, diseases that reduce blood flow to specific tissues and organs will result in less drug being delivered to those tissues.25 3. Binding to plasma proteins. Certain drugs will form reversible bonds to circulating proteins in the bloodstream such as albumin.86 This fact is significant because only the unbound or free drug is able to reach the target tissue and exert a pharmacologic effect. Basically, the fraction of the drug that remains bound to the circulating proteins is sequestered within the vascular system and not available for therapeutic purposes in other tissues and organs. 4. Binding to subcellular components. In a situation similar to plasma protein binding, drugs that are bound within specific cells are unable to leave the cell and be distributed throughout other fluid compartments. Several drugs, for example, bind to subcellular organelles such as the lysosome, thus trapping the drug within the cell. Examples of this type of subcellular binding include certain antidepressants, antipsychotics, and other drugs with a relatively high pH that are attracted by the acidic environment found inside the lysosome.24,88

Volume of Distribution
The distribution of a given drug within the body is often described by calculating the volume of distribution (Vd) for that drug.8,86 Vd is the ratio of the


SECTION 1 General Principles of Pharmacology

amount of drug administered to the concentration of drug in the plasma: Vd amount of drug administered concentration of drug in plasma. Vd is used to estimate a drugs distribution by comparing the calculated Vd with the total amount of body water in a normal person. A normal 70 kg man has a total body fluid content of approximately 42 L (5.5 L blood, 12.0 L extracellular fluid, 24.5 L intracellular fluid). If the calculated Vd of a drug is approximately equal to the total amount of body water, then the drug is distributed uniformly throughout all of the bodys fluids. If the Vd of the drug is far less than 42 L, then the drug is being retained in the bloodstream due to factors such as plasma protein binding. A Vd much greater than 42 L indicates that the drug is being concentrated in the tissues. It should be noted that Vd is not a real value; that is, it does not indicate the actual amount of fluid in the body, but is merely an arbitrary figure that reflects the apparent distribution of a drug using total body water as a reference point. Table 22 gives some examples of the calculation of the Vd for three different types of drugs.

tively inert tissue that may be different from the target site of the drug. Some storage sites include the following: 1. Adipose. The primary site for drug storage in the body is adipose tissue. Because many drugs are lipid soluble, fat deposits throughout the body can serve as a considerable reservoir for these compounds. In some individuals, the amount of fat in the body can reach as high as 40 to 50 percent of body weight, thus creating an extensive storage compartment. Once drugs have been stored in adipose tissue, they tend to remain there for long periods of time because of the low metabolic rate and poor blood perfusion of these tissues. Examples of drugs that tend to be stored in fat include highly lipidsoluble anesthetics such as the barbiturates (thiopental) and inhalation anesthetics (halothane). 2. Bone. Bone acts as a storage site for several toxic agents, especially heavy metals like lead. Also, drugs such as the tetracyclines, which bind to and form molecular complexes with the crystal components within the skeletal matrix, are stored within bone. 3. Muscle. Binding of drugs to components within the muscle may create the long-term storage of these compounds. Various agents may be actively transported into the muscle cell and may form reversible bonds to intracellular structures such as proteins, nucleoproteins, or phospholipids. An example is the antimalarial drug quinacrine.

Drug Storage
Storage Sites
Following administration and absorption, many drugs are stored to some extent at certain locations in the body86; that is, prior to drug elimination, the drug may be sequestered in its active form in a rela-

Table 22
Drug A


Plasma Volume of Concentration Distribution 0.01 mg/mL 420 mg 0.01 mg/mL 42,000 mL 42 L 420 mg 0.05 mg/mL 8400 mL 8.4 L 420 mg 0.001 mg/mL 420,000 mL 420 L Indication Uniform distribution Examples Erythromycin; lithium

Amount Administered 420 mg

420 mg

0.05 mg/mL

Retained in plasma

Aspirin; valproic acid

420 mg

0.001 mg/mL

Sequestered in tissues

Morphine; quinidine

Chapter 2 Pharmacokinetics I


4. Organs. Drugs are often stored within certain organs such as the liver and kidneys. As in muscle cells, the drug may enter the cell passively or by active transport and then form bonds to subcellular components. Examples include antimicrobial aminoglycoside agents (such as gentamicin and streptomycin), which accumulate in renal proximal tubular cells.

redistribution may explain why certain individuals experience prolonged effects of the drug or extended adverse side effects.

Newer Techniques for Drug Delivery

Controlled-Release Preparations
Controlled-release preparations, also known as timed-release, sustained-release, extended-release, or prolonged-action preparations, are generally designed to permit a slower and more prolonged absorption of the drug from the gastrointestinal tract and other routes of administration.86 This technique may offer several advantages such as decreasing the number of doses needed each day, preventing large fluctuations in the amount of drug appearing in the plasma, and sustaining plasma levels throughout the night.13,37 This type of preparation has been used successfully with several types of drugs, including cardiovascular medications (beta blockers, calcium channel blockers),26,77 narcotic analgesics such as morphine,13,28 and anti-Parkinson medications that contain L-dopa.46,75 Controlledrelease preparations will probably continue to gain popularity as a means for administering these and other medications in the future.86

Adverse Consequences of Drug Storage

High concentrations of drugs, drug metabolites, and toxic compounds within tissues can cause local damage to the tissues in which they are stored. This event is particularly true for toxic compounds that are incorporated and stored in the matrix of bone or that are highly concentrated within specific organs. Lead poisoning, for example, causes several well-known and potentially devastating effects when this metal accumulates, in the CNS, bone, GI tract, and several other tissues. Exposing various organs to high concentrations of therapeutic drugs can also result in myriad problems. Actaminophen, for example, is normally metabolized in the liver to form several highly reactive by-products or metabolites (see Chapter 15). When normal doses of acetaminophen are metabolized in a reasonably healthy liver, these metabolites are rapidly inactivated in the liver and subsequently excreted by the kidneys. Very high doses of acetaminophen, however, result in the formation of excessive amounts of a toxic metabolite that can react with hepatic proteins and cause severe liver damage.64 Hence, organs such as the liver and the kidneys are often subjected to local damage when these organs must deal with high concentrations of therapeutic and toxic agents. Another problem with drug storage occurs when the storage site acts as a reservoir that soaks up the drug and prevents it from reaching the target site. For instance, a highly lipid-soluble drug such as a general anesthetic must be administered at a sufficient dose to ensure that there will be enough drug available to reach the CNS, despite the tendency for much of the drug to be sequestered in the bodys fat stores. Storage sites may also be responsible for the redistribution of drugs. This occurrence is seen when the drug begins to leak out of the storage reservoir after plasma levels of the drug have begun to diminish. In this way, the drug may be reintroduced to the target site long after the original dose should have been eliminated. This

Implanted Drug Delivery Systems

Several techniques have been developed whereby a type of drug reservoir is implanted surgically within the body and is then released in a controlled fashion from the implanted reservoir.38,76 These drug reservoirs typically consist of a small container placed under the skin in the abdomen. The containers are often programmed to allow a small, measured dose of the drug to be released periodically from the reservoir. Alternatively, the reservoir can be controlled electronically from outside of the body through the use of small, remote-controlled devices, thus allowing the patient to regulate release of the drug as needed. In some cases, the drug reservoir may be connected by a small cannula to a specific body compartmentsuch as the subarachnoid space or epidural spaceso that the drug can be delivered directly into that space. This type of system appears to be very helpful in applying certain drugs such as analgesics, anesthetics, and muscle relaxants into the spinal cord.29,38,76


SECTION 1 General Principles of Pharmacology

Another type of implantable system has been developed recently that incorporates the drug into some type of biodegradable or nonbiodegradable substance such as a polymer matrix or gel.53,57,71 The drug-polymer complex is then implanted in the body and the drug is slowly released into surrounding tissues (nonbiodegradable), or is released as the matrix gradually dissolves (biodegradable). This type of system is probably best known for administering contraceptive hormones such as progesterone (Norplant; see Chapter 30); these implants have also shown promise in delivering other medications such as local anesthetics, insulin, and vaccines.71 Hence, implantable drug delivery systems are being considered as a potential means of administering several drugs including analgesics, muscle relaxants, and hormones. Improvements in the technology of this type of drug delivery will hopefully permit increased clinical applications of these systems in the near future. The use of implantable drug delivery systems with specific types of medications will be discussed in more detail when these medications are addressed in subsequent chapters in this book.

Targeting Drug Delivery to Specific Cells and Tissues

Some very innovative approaches have been attempted on a molecular level to try to target the drug specifically to the cells that require treatment. For instance, specific types of antibodies (monoclonal antibodies) can be synthesized and attached to certain drugs such as the cytotoxic agents often used in cancer chemotherapy.1,32 The antibodies are then attracted to antigens located on the surface of the tumor cells. This offers the distinct advantage of focusing the drug more directly on the cancerous cells rather than on healthy human tissues. Other cellular techniques have been investigated that could also help direct the drug to the affected tissues. It may be possible, for example, to link a drug to a modified virus so that the virus transports and helps insert the drug directly into specific cells;47,51 the virus, of course, must be modified so that it will not cause viral infection. Other nonviral techniques include encapsulating the drug in a certain type of fat particle (liposome) or attaching the drug to certain proteins that will be attracted to the surface receptors of specific cells.14,48 These viral and nonviral tech-

niques have been particularly important in helping deliver DNA to specific cells in order to modify the genetic regulation of those cells (gene-based therapy).47,48,51 Drugs can also be targeted to specific sites by capitalizing on unique physiologic properties of various tissues and organs. Certain drugs, for example, might be activated by enzymes that are found only in the kidneys, thereby targeting these drugs specifically to the kidneys.31 Abnormal tissues, including some tumors, might also have specialized enzymes that could be used to activate certain drugs only after the drugs reach these tissues.68 Various techniques can also be used to modify a drug so that it is activated only after reaching the colon.15,16 This action will allow the drug to be administered orally, but remain inactive as a prodrug until it reaches the colon, where it will then become activated to treat local problems or be absorbed into the systemic circulation.33,72 The idea of targeting drugs to specific tissues through various cellular and chemical mechanisms is still relatively new. These techniques have shown considerable promise, however, and may ultimately be extremely useful in increasing the effectiveness of certain drugs while decreasing side effects.

In order for any drug to be effective, it must be able to reach specific target tissues. The goal of drug administration is to deliver the drug in the least complicated manner while still allowing sufficient concentrations of the active form of the drug to arrive at the desired site. Each route of administration has certain advantages and disadvantages that will determine how much and how fast the drug is delivered to specific tissues. In addition to the route of administration, the distribution of the drug within the body must be taken into account. Simply introducing the drug into certain body fluids such as the bloodstream does not ensure its entry into the desired tissues. Factors such as tissue permeability and protein binding may influence how the drug is dispersed within the various fluid compartments within the body. Finally, some drugs have a tendency to be stored in certain tissues for prolonged periods of time. This storage may produce serious toxic effects if high concentrations of the compound damage the cells in which it is stored.

Chapter 2 Pharmacokinetics I


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41. Kutchai HC. Cellular membranes and transmembrane transport of solutes and water. In: Berne RM, Levy MN, eds. Principles of Physiology. 3rd ed. St Louis, MO: CV Mosby; 2000. 42. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:600612. 43. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:588599. 44. Langer R. Transdermal drug delivery: past progress, current status, and future prospects. Adv Drug Deliv Rev. 2004;56:557558. 45. Lesage F. Pharmacology of neuronal background potassium channels. Neuropharmacology. 2003;44:17. 46. LeWitt PA, Nyholm D. New developments in levodopa therapy. Neurology. 2004;62(suppl 1):S9S16. 47. Lundstrom K. Latest development in viral vectors for gene therapy. Trends Biotechnol. 2003;21:117122. 48. Lundstrom K, Boulikas T. Viral and non-viral vectors in gene therapy: technology development and clinical trials. Technol Cancer Res Treat. 2003;2:471486. 49. Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral delivery of peptide and protein drugs. Crit Rev Ther Drug Carrier Syst. 2003; 20:153214. 50. Martens JR, OConnell K, Tamkun M. Targeting of ion channels to membrane microdomains: localization of KV channels to lipid rafts. Trends Pharmacol Sci. 2004;25:1621. 51. Mata M, Glorioso JC, Fink DJ. Targeted gene delivery to the nervous system using herpes simplex virus vectors. Physiol Behav. 2002;77:483488. 52. Maxfield FR. Plasma membrane microdomains. Curr Opin Cell Biol. 2002;14:483487. 53. Meirik O, Fraser IS, dArcangues C. WHO Consultation on Implantable Contraceptives for Women. Implantable contraceptives for women. Hum Reprod Update. 2003;9:4959. 54. Mercadante S, Fulfaro F. Alternatives to oral opioids for cancer pain. Oncology. 1999;13:215229. 55. Miles J. Intrathecal treatment for spasticity. Stereotact Funct Neurosurg. 2001;76:246248. 56. Mitragotri S. Synergistic effect of enhancers for transdermal drug delivery. Pharm Res. 2000;17:13541359. 57. Moses MA, Brem H, Langer R. Advancing the field of drug delivery: taking aim at cancer. Cancer Cell. 2003; 4:337341. 58. Murphy M, Carmichael AJ. Transdermal drug delivery systems and skin sensitivity reactions. Incidence and management. Am J Clin Dermatol. 2000;1:361368. 59. Nelson EA, Bradley MD. Dressings and topical agents for arterial leg ulcers. Cochrane Database Syst Rev. 2003; CD001836. 60. Penn RD. Intrathecal medication delivery. Neurosurg Clin N Am. 2003;14:381387. 61. Pereira LO, Lancha AH Jr. Effect of insulin and contraction up on glucose transport in skeletal muscle. Prog Biophys Mol Biol. 2004;84:127.

Chapter 2 Pharmacokinetics I 81. Triggle DJ. Drug targets in the voltage-gated calcium channel family: why some are and some are not. Assay Drug Dev Technol. 2003;1:719733. 82. Ulrich AS. Biophysical aspects of using liposomes as delivery vehicles. Biosci Rep. 2002;22:129150. 83. van Montfoort JE, Hagenbuch B, Groothuis GM, et al. Drug uptake systems in liver and kidney. Curr Drug Metab. 2003;4:185211. 84. Wang SY, Wang GK. Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins. Cell Signal. 2003;15:151159. 85. Webster GF. Topical medications: a focus on antifungals and topical steroids. Clin Cornerstone. 2001;4: 3338. 86. Wilkinson GR. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: Hardman JG, et al eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001.


87. Wilson CG. Topical drug delivery in the eye. Exp Eye Res. 2004;78:737743. 88. Yokogawa K, Ishizaki J, Ohkuma S, Miyamoto K. Influence of lipophilicity and lysosomal accumulation on tissue distribution kinetics of basic drugs: a physiologically based pharmacokinetic model. Methods Find Exp Clin Pharmacol. 2002; 24:8193. 89. You G. The role of organic ion transporters in drug disposition: an update. Curr Drug Metab. 2004;5: 5562. 90. Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet. 2002;41: 661680. 91. Zhorov BS, Tikhonov DB. Potassium, sodium, calcium and glutamate-gated channels: pore architecture and ligand action. J Neurochem. 2004;88:782799.

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Pharmacokinetics II: Drug Elimination

All drugs must be eliminated from the body eventually to terminate their effect and to prevent excessive accumulation of the drug. Drugs are usually eliminated by chemically altering the original compound while it is still in the body so that it is no longer active (biotransformation), by excreting the active form of the drug from the body (excretion), or by a combination of biotransformation and excretion. These methods of drug elimination will be discussed here. must eventually wear off, allowing the patient to resume normal functioning. Although termination of drug activity can occur when the active form of the drug is excreted from the body via organs such as the kidneys, excretory mechanisms are often too slow to effectively terminate any activity within a reasonable time period. If excretion were the only way to terminate drug activity, some compounds would continue to exert their effects for several days or even weeks. Drug biotransformation into an inactive form usually occurs within a matter of minutes or hours, thus reducing the chance for toxic effects caused by drug accumulation or prolonged drug activity.

Drug metabolism, or biotransformation, refers to chemical changes that take place in the drug following administration. Enzymes that are located within specific tissues are responsible for catalyzing changes in the drugs structure and subsequently altering the pharmacologic properties of the drug. The location of these enzymes and the reactions involved in biotransformation are discussed later in this chapter. Biotransformation usually results in an altered version of the original compound known as a metabolite, which is usually inactive or has a greatly reduced level of pharmacologic activity. Occasionally, the metabolite has a higher level of activity than the original compound. In these cases, the drug may be given in an inactive, or prodrug, form that will activate via biotransformation following administration. However, after it has exerted its pharmacologic effect, drug termination is the primary function of biotransformation.53 Inactivating a drug and terminating its effects after it is no longer needed are often essential. For instance, the effects of general and local anesthetics

Cellular Mechanisms of Drug Biotransformation

The chemical changes that occur during drug metabolism are usually caused by oxidation, reduction, hydrolysis, or conjugation of the original compound.28,52,60 Examples of each type of reaction are listed in Table 31. Each type of reaction and the location of the enzymes catalyzing the reaction are also discussed here. 1. Oxidation. Oxidation occurs when either oxygen is added or hydrogen is removed from the original compound. Oxidation reactions comprise the predominant method of drug biotransformation in the body, and the primary enzymes that catalyze these reactions are known collectively as the cytochrome P450 monooxygenases.27,28,52 These enzymes are primarily located on the smooth endoplasmic reticulum of specific cells and are sometimes referred to as the drug


SECTION 1 General Principles of Pharmacology

Table 31
I. Oxidation



A. Side chain (aliphatic) hydroxylation OH [O] RCH2CH3RCHCH3 B. N-oxidation [O] (R)2NH(R)2NOH C. Deamination [O] RCH2NH2RCHO NH3 II. Reduction A. Nitro reductions RNO2RNH2 B. Carbonyl reductions O OH RCR RCHR III. Hydrolysis A. Esters O RCORRCOOH B. Amides O RCNRRCOOH IV. Conjugation A. Acetylation O RNH2 AcetylCoA RNHCCH3 B. Glycine conjugation O RCOOHRCSCoA O RCNHCH2COOH CoA-SH ROH










NH2CH2COOH CoA-SH Benzoic acid

Parent drug compounds are represented by the letter R. Examples are types of drugs that undergo biotransformation via the respective type of chemical reaction.

microsomal metabolizing system (DMMS). The general scheme of drug oxidation as catalyzed by the DMMS is shown in Figure 31. 2. Reduction. Reduction reactions consist of removing oxygen or adding hydrogen to the original

compound. Enzymes that are located in the cell cytoplasm are usually responsible for drug reduction. 3. Hydrolysis. The original compound is broken into separate parts. The enzymes responsible

Chapter 3 Pharmacokinetics II: Drug Elimination

DMMS Enzymes


Parent Drug


+ 2H

Oxidized Metabolite

+ H2O

FIGURE 31 Drug oxidation catalyzed by drug microsomal metabolizing system (DMMS) enzymes.

neys, gastrointestinal epithelium, and skin. Drug metabolism can be radically altered in conditions where these tissues are damaged. For instance, inactivation of certain drugs may be significantly delayed in the patient with hepatitis or cirrhosis of the liver.47,61 As expected, dosages in these patients must be adjusted accordingly to prevent drug accumulation and toxicity.

for the hydrolysis of the drug are located at several sites within the cell (i.e., the endoplasmic reticulum and cytoplasm) as well as extracellularly (e.g., circulating in the plasma). 4. Conjugation. In conjugation reactions, the intact drug or the metabolite of one of the reactions described earlier, is coupled to an endogenous substance such as acetyl coenzyme A (acetyl CoA), glucuronic acid, or an amino acid. Enzymes catalyzing drug conjugations are found in the cytoplasm and on the endoplasmic reticulum. The chemical reactions involved in drug biotransformation are also classified as either phase I or phase II reactions.27,28,52,60 Phase I reactions consist of those using oxidation, reduction, or hydrolysis. Phase II reactions involve conjugation of the parent drug or the metabolite of a drug that was already metabolized using a phase I reaction. Regardless of the type of chemical reaction used, biotransformation also helps in metabolite excretion from the body by creating a more polar compound.18,53,60 After one or more of the reactions just described occurs, the remaining drug metabolite usually has a greater tendency to be ionized in the bodys fluids. The ionized metabolite is more water soluble, thus becoming transported more easily in the bloodstream to the kidneys. Upon reaching the kidneys, the polar metabolite can be excreted from the body in the urine. The contribution of biotransformation toward renal excretion is discussed in a later section.

Enzyme Induction
A frequent problem in drug metabolism is the phenomenon of enzyme induction.9,13,62 Prolonged use of certain drugs induces the body to be able to enzymatically destroy the drug more rapidly, usually because either more metabolizing enzymes are being manufactured or less are being degraded. Enzyme induction may cause drugs to be metabolized more rapidly than expected, thus decreasing their therapeutic effect. This may be one reason why tolerance to some drugs occurs when it is used for extended periods (tolerance is the need for increased drug dosages to produce the same effect). Long-term ingestion or inhalation of other exogenous compounds such as alcohol, cigarette smoke, or environmental toxins may also cause enzyme induction.9,39,49 When this occurs, medicinal drugs may be more rapidly metabolized even when they are first administered because of the preexisting enzyme induction.

Drug Excretion
The kidneys are the primary sites for drug excretion.33,56 The functional unit of the kidney is the nephron (Fig. 32), and each kidney is composed of approximately 1 million nephrons. Usually, the metabolized or conjugated version of the original drug reaches the nephron and is then filtered at the glomerulus. Following filtration, the compound traverses the proximal convoluted tubule, loop of Henle, and distal convoluted tubule before reaching the collecting ducts. If a compound is not reabsorbed while moving through the nephron, it will ultimately leave the body in the urine. As discussed earlier, biotransformation plays a significant role in creating a polar, water-soluble metabolite that is able to reach the kidneys through the bloodstream. Only relatively polar drugs or their metabolites will be excreted in significant amounts by the kidneys because the ionized metabolite has a greater tendency to remain in the nephron and not be reabsorbed into the body.60 Nonpolar compounds that are filtered by the kidneys are

Organs Responsible for Drug Biotransformation

The primary location for drug metabolism is the liver.5,60 Enzymes responsible for drug metabolism, such as the cytochrome P450 enzymes, are abundant on hepatic smooth endoplasmic reticulum; liver cells also contain other cytoplasmic enzymes responsible for drug reduction and hydrolysis. Other organs that contain metabolizing enzymes and exhibit considerable drug transformation abilities include the lungs, kid-


SECTION 1 General Principles of Pharmacology

glomerulus proximal tubule loop of Henle distal tubule collecting duct




Polar metabolite Nonpolar compound


FIGURE 32 Drug excretion at the nephron. Compounds reach the nephron by filtration and/or secretion. Polar metabolites remain trapped in the nephron and are eventually excreted. Nonpolar compounds are able to diffuse back into the body (reabsorption).

relatively lipophilic and can easily be reabsorbed back into the body passively by diffusing through the wall of the nephron. However, the polar metabolite is relatively impermeable to the epithelium lining, and the metabolite tends to remain trapped in the nephron following filtration, where it will eventually be excreted in the urine (see Fig. 32). In addition to filtration, some drugs may be secreted into the nephron by active transport mechanisms located in the proximal convoluted tubule. Several distinct types of transport proteins have been identified that secrete substances such as organic cations (e.g., uric acid), organic anions (e.g., choline, histamine), prostaglandins, conjugated drug metabolites, and a variety of other compounds.25,42,33 Certain drugs can also be transported by one of these carrier systems so that they are actively secreted into the nephron. For example, penicillin G is actively secreted via the transport system for organic acids, and morphine is secreted by the organic base transport system. In these cases, elimination of the drug is enhanced by the combined effects of tubular secretion and filtration in delivering the drug to the urine. Other routes for drug excretion include the lungs and gastrointestinal tract. The lungs play a significant role in excreting volatile drugs, that is, drugs that are usually administered by inhalation. Consequently, the lungs serve as the route of both administration and

excretion for drugs such as gaseous anesthetics. The gastrointestinal tract usually plays only a minor role in drug excretion. Certain drugs can be excreted by the liver into the bile and subsequently reach the duodenum via the bile duct. If the drug remains in the gastrointestinal tract, it will eventually be excreted in the feces. However, most of the secreted bile is reabsorbed, and drugs contained in it are often reabsorbed simultaneously. Other minor routes for drug excretion include the sweat, saliva, and breast milk of lactating mothers. Although drugs excreted via lactation are considered a relatively minor route with regard to loss from the mother, the possibility that the infant may imbibe substantial concentrations of the drug does exist. Careful consideration for the welfare of the nursing infant must always be a factor when administering medications to the lactating mother.10,21

Drug Elimination Rates

The rate at which a drug is eliminated is significant in determining the amount and frequency of the dosage of the drug. If a drug is administered much faster than it is eliminated, the drug will accumulate excessively in the body and reach toxic levels. Conversely, if elimination greatly exceeds the rate of delivery, the concen-

Chapter 3 Pharmacokinetics II: Drug Elimination


tration in the body may never reach therapeutic levels. Several parameters are used to indicate the rate at which a drug is usually eliminated so that dosages may be adjusted accordingly. Two of the primary measurements are clearance and half-life.58,60

Clearance of a drug (CL) can be described either in terms of all organs and tissues ability to eliminate the drug (systemic clearance) or in terms of a single organ or tissues ability to eliminate the drug.7,38,60 To calculate clearance from a specific organ, two primary factors must be considered. First, the blood flow to the organ (Q) determines how much drug will be delivered to the organ for elimination. Second, the fraction of drug removed from the plasma as it passes through the organ must be known. This fraction, termed the extraction ratio, is equal to the difference in the concentration of drug entering (Ci) and exiting (Co) the organ, divided by the entering concentration (Ci). Clearance by an individual organ is summarized by the following equation: CL Q [(Ci Co) Ci].

amount of blood reaches the organ. Conversely, highly perfused organs may be ineffective in removing the drug, thus prolonging its activity. In terms of drug elimination from the entire body, systemic clearance is calculated as the sum of all individual clearances from all organs and tissues (i.e., systemic CL hepatic CL renal CL lung CL, and so on). Note that the elimination of the drug includes the combined processes of drug loss from the body (excretion) as well as inactivation of the drug through biotransformation.7,58,60

In addition to clearance, the half-life of the drug is important in describing the duration of activity of the compound. Half-life is defined as the amount of time required for 50 percent of the drug remaining in the body to be eliminated.59,60 Most drugs are eliminated in a manner such that a fixed portion of the drug is eliminated in a given time period. For example, a drug such as acetaminophen with a half-life of 2 hours indicates that in each 2-hour period, 50 percent of the acetaminophen still in the body will be eliminated (Fig. 33). Half-life is a function of both clearance and volume of distribution (Vd);38 that is, the time it takes to eliminate 50 percent of the drug depends not only on the ability of the organ(s) to remove the drug from the plasma, but also on the distribution or presence

The calculation of clearance using this equation is illustrated by the following example. Aspirin is metabolized primarily in the liver. Normal hepatic blood flow (Q) equals 1500 mL/min. If the blood entering the liver contains 200 g/mL of aspirin (Ci) and the blood leaving the liver contains 134 g/mL (Co), hepatic clearance of aspirin is calculated as follows: CLhepatic Q [(Ci Co) Ci] 134

Plasma Concentration of Drug (%)


1500 mL/min [(200 g/mL g/mL) 200 g/mL] 495 mL/min.


This example illustrates that clearance is actually the amount of plasma that the drug can be totally removed from per unit time. As calculated here, the liver would be able to completely remove aspirin from 495 mL of blood each minute. Tetracycline, a common antibacterial drug, has a clearance equal to 130 mL/min, indicating that this drug would be completely removed from approximately 130 mL of plasma each minute. Clearance is dependent on the organ or tissues ability to extract the drug from the plasma as well as the perfusion of the organ. Some tissues may have an excellent ability to remove the drug from the bloodstream, but clearance is limited because only a small



0 1 2 3 4 5 6 Time (hours)
FIGURE 33 Elimination of a drug with a half-life of 2 hours. Fifty percent of the drug remaining in the bloodstream is eliminated in each 2-hour period.


SECTION 1 General Principles of Pharmacology

of the drug in the plasma (see Chapter 2 for a description of Vd). A drug that undergoes extensive inactivation in the liver may have a long half-life if it is sequestered intracellularly in skeletal muscle. Also, disease states that affect either clearance or Vd will affect the half-life of the drug, so dosages must be altered accordingly.

more frequently provides an equivalent average concentration without the extreme peaks and valleys associated with longer intervals.

Variations in Drug Response and Metabolism

The fact that different people react differently to the same relative drug dosage is an important and often critical aspect of pharmacology. Two patients who are given the same drug may exhibit different magnitudes of a beneficial response as well as different adverse effects. Several primary factors that are responsible for variations in the response to drugs are discussed below. 1. Genetic factors. Genetic variability can result in altered drug pharmacokinetics in certain individuals. In extreme cases, genetic variations may result in abnormal or absent drug-metabolizing enzymes.60 This deficiency can be harmful or even fatal if the drug is not metabolized and begins exerting toxic effects due to accumulation or prolonged pharmacologic activity. For example, some individuals lack the appropriate plasma cholinesterase to break down circulating acetylcholine and acetylcholine-like compounds.55 Succinylcholine is a neuromuscular blocking agent that is usually administered during general anesthesia to ensure muscular relax-

Dosing Schedules and Plasma Concentration

With most medications, it is desirable to bring plasma concentrations of the drug up to a certain level and maintain it at that level. If the drug is administered by continuous intravenous administration, this can be done fairly easily by matching the rate of administration with the rate of drug elimination (clearance) once the desired plasma concentration is achieved (Fig. 34). In situations where the drug is given at specific intervals, the dosage must be adjusted to provide an average plasma concentration over the dosing period. Figure 34 illustrates that if the dosing interval is relatively long (e.g., 12 hours), the dose must be considerably large to provide the same relative plasma concentration that would exist in a shorter dosing interval (e.g., 8 hours). Note also that larger doses given further apart result in greater plasma fluctuations; that is, greater maximum and minimum plasma levels over the dosing period. Giving smaller doses
(From Katzung BG. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw-Hill; 2004, with permission.)

Plasma concentration (mg/L)















Time (hours)

FIGURE 34 Relationship between dosing interval and plasma concentrations of the antiasthmatic drug theophylline. A constant intravenous infusion (shown by the smoothly rising line) yields a desired plasma level of 10 mg/L. The same average plasma concentration is achieved when a dose of 224 mg is taken every 8 hours, or a dose of 672 mg every 24 hours. However, note the fluctuations in plasma concentration seen when doses are taken at specific hourly intervals.

Chapter 3 Pharmacokinetics II: Drug Elimination


ation during surgery. Normally, the succinylcholine is quickly degraded by plasma cholinesterase; however, individuals lacking the appropriate form of cholinesterase may suffer respiratory paralysis because the succinylcholine exerts its effect much longer than the expected period of time. In addition to the extreme case described above, we now realize that many people have subtle but important differences in the genes controlling the synthesis of many drug-related proteins. These differencesknow as genetic polymorphismswill result in the production of proteins that are somewhat different in structure and function.32,40,45 From this, various aspects of drug disposition and response will be affected.3,23,29 For example, differences in proteins that transport drugs across membranes will result in altered absorption, distribution, and excretion of drugs using these transport systems. Differences in the genetic control of drug metabolizing proteins (enzymes) will likewise result in altered metabolism and biotransformation of specific drugs. Finally, differences in the proteins that function as drug receptors on specific cells and target tissues (see Chapter 4) might cause variability in the tissues responses. The potential influence of genetic variability on drug responses and metabolism has actually evolved into a branch of genetics known as pharmacogenetics, or pharmacogenomics.15 Research in pharmacogenetics will continue to expand as more details emerge about human genetic make-up (i.e., the human genome project). We can tailor drug therapy more specifically for patients by realizing how specific genetic differences might influence drug responses.15,20,29,40 That is, doses can be adjusted to account for genetic differences in drug disposition, and certain drugs can be avoided altogether in people who lack the appropriate enzymes for these drugs. Drug regimens that take into account genetic variability will ultimately result in better drug effects with fewer side effects. 2. Disease. Structural or functional damage to an organ or tissue responsible for drug metabolism or excretion presents an obvious problem in pharmacology. Diseases initiating change in tissue function or blood flow to specific organs like the liver and kidneys can dramatically affect the elimination of various drugs.44,47,60 Certain dis-

eases may also impair the absorption and distribution of the drug, further complicating the problem of individualized response. The significance of disease in affecting the patients response is crucial since response to a medication may be affected by the very same pathology that the drug is being used to treat. For instance, renal excretion of antibiotics, such as the aminoglycosides, is altered radically in many types of bacterial infection, but these drugs are typically administered to treat the same infections altering their own excretion.60 Consequently, great care must be taken to adjust the dosage accordingly when administering medications in conditions where drug disposition might be altered by various diseases.24,47,60 3. Drug interactions. When two or more drugs are present in the body at the same time, the chance exists that they may interact and alter each others effects and metabolism.2,19 The majority of drug-drug interactions are insignificant and do not result in any clinically meaningful adverse effects.11,46 Likewise, certain drug combinations and interactions can be beneficial because two or more compounds might act synergistically to produce a cumulative effect that is greater than each drug would produce alone. Several drugs, for example, are often administered simultaneously so that they augment each other when treating conditions such as hypertension, cancer, and human immunodeficiency virus infection. However, certain combinations can lead to serious adverse effects and interactions. For example, two or more drugs can have additive effects that cause an adverse response, even if each drug is given in a nontoxic dose. For instance, taking two central nervous system (CNS) depressants simultaneously (e.g., barbiturates and alcohol) may cause such severe CNS inhibition that the additive effects are lethal. In contrast to an additive effect, drugs with opposite actions may essentially cancel each other out, thus negating or reducing the beneficial effects of one or both medications. A drug that causes bronchodilation (i.e., for the treatment of asthma) will be negated by an agent that constricts the bronchioles. Some of the most serious problems occur during drug interactions because one drug delays the biotransformation of the other. If a second compound inhibits the enzymes that


SECTION 1 General Principles of Pharmacology

normally metabolize a drug, the original drug will exert its effect for prolonged periods, possibly leading to toxic effects.60 For instance, the antiulcer drug cimetidine (Tagamet) inhibits the hepatic metabolism of oral anticoagulants such as warfarin (Coumadin). Taking these two drugs together tends to cause elevated plasma levels of the anticoagulant, which may prolong blood clotting and lead to a possible hemorrhage. Another type of interaction occurs when two or more drugs alter each others absorption and distribution, and can occur when they compete for the same active transport carrier or bind to the same plasma proteins. An example is the interaction between aspirin and methotrexate, a drug used to treat cancer and rheumatoid arthritis. Aspirin can displace methotrexate from its binding site on plasma proteins, thus allowing relatively high amounts of unbound or free methotrexate to exist in the bloodstream. The increased levels of free methotrexate may lead to toxic effects. Considering the large number of drugs on the market, it is well beyond the scope of this text to discuss all of the clinically relevant drug interactions. The prescribing physician and pharmacist, however, must carefully evaluate the potential for drug interactions. Likewise, physical therapists, occupational therapists, and other individuals dealing with patients taking medications must be alert for any abnormal symptoms or untoward effects because they may indicate a possible drug interaction. 4. Age. In general, older patients are more sensitive to drugs.8,37 Drugs are usually not metabolized as quickly in the elderly, primarily because of decreases in liver and kidney function that typically accompany the aging process.31,48,57 Decreased drug elimination therefore results in higher plasma levels in older adults than those occurring in younger adults given equivalent doses.31,63 Older adults also suffer more illnesses, and consequently receive more drugs than younger adults; this fact further increases their vulnerability to altered drug responses.4 Various other age-related changes in physiology (increased body fat, decreased cardiovascular function, and so forth) can affect pharmacokinetics and pharmacodynamics in older adults.8,57 Children are also subject to problems and variability in drug metabolism.54 Because liver

and kidney function is immature, newborns may be deficient in specific drug-metabolizing enzymes, thus prolonging the effects of drugs.1,16,22 Infants also differ from adults in several other key factors affecting drug disposition including differences in membrane function, plasma proteins, regional blood flow, and body composition (i.e., percentage of body fat and total body water).54 Hence, drug absorption, distribution, and elimination will be altered in infants, and these alterations will be especially problematic in infants who are born prematurely. 5. Diet. Diet is shown to affect the absorption, metabolism, and response to many drugs.12,30 Animal and human studies indicated that the total caloric input as well as the percentage of calories obtained from different sources (carbohydrates, proteins, and fats) influence drug pharmacokinetics.17,26 Specific dietary constituents such as cruciferous vegetables and charcoal-broiled beef can also alter drug metabolism.17 Fortunately, most food-drug interactions are not serious and will not alter the clinical effects of the drug. There are, however, a few wellknown food-drug combinations that should be avoided because of their potentially serious interaction. For example, it was recently discovered that grapefruit juice inhibits the enzymes that metabolize certain drugs as they are absorbed from the gastrointestinal (GI) tract. As a result, taking these drugs orally with grapefruit juice will result in increased drug bioavailability because more of the drugs active form will reach the bloodstream.12,19 This increased bioavailability will result in plasma levels that are higher than expected, thereby increasing the risk of side effects and adverse reactions. Another important food-drug interaction involves certain foods such as fermented cheese and wine. These foods contain high amounts of tyramine, which stimulates the release of catecholamines (norepinephrine, epinephrine) within the body. Hence, these foods should not be ingested with drugs that inhibit the monoamine oxidase enzyme (MAO inhibitors). MAOinhibiting drugs work by suppressing the destruction of catecholamines, thus allowing higher levels of norepinephrine and epinephrine to occur. (MAO inhibitors are frequently

Chapter 3 Pharmacokinetics II: Drug Elimination


used in the treatment of depression; see Chapter 7.) Consequently, when MAO inhibitors are taken with tyramine-containing foods, excessive levels of catecholamines may develop, leading to a dangerous increase in blood pressure (hypertensive crisis). A number of other potential food-drug interactions occur, but it is beyond the scope of this text to discuss all of them. These interactions are addressed in more detail elsewhere.19,30,34 Clinicians should therefore be aware of these well-known interactions and be on the alert for others as new drugs arrive on the market. 6. Sex Men and women may have distinct differences in the way that certain drugs are absorbed, distributed, and metabolized.14,35,50 This idea makes sense when one considers that sex-related differences in body composition, gastrointestinal function, enzyme activity, and various other systems can potentially affect pharmacokinetic variables.14,35,50 Drug disposition may also be influenced in women by the cyclic hormonal variations occurring during the menstrual cycle, whereas men do not typically undergo such routine hormonal fluctuations.14 Pharmacokinetics can clearly differ between men and women, and future research is needed to determine how sex-related differences affect the therapeutic outcomes of specific drugs.14,50 7. Other factors. A number of additional factors may alter the predicted response of the patient to a drug. As discussed earlier, environmental and occupational hazards may produce certain toxins that alter drug absorption and metabolism .9,62 Factors such as cigarette smoking and alcohol consumption have been shown to influence the metabolism of specific compounds.39,49 Drug distribution and metabolism may be altered in the obese patient,6 or in response to chronic and acute exercise.7,43 Individuals with spinal cord injuries have a decreased ability to absorb cer-

tain drugs from their gastrointestinal tract, presumably because of a general decrease in gastrointestinal motility.51 Conversely, patients with extensive burn injuries may have increased gastrointestinal absorption and therefore increased bioavailability of certain drugs, although the reason for this effect is not clear.36,41 There are many factors that influence the way each individual responds to a medication, and these factors must be taken into account whenever possible. Clinicians should also realize that these factors are not mutually exclusive. For example, a premature infant with genetic polymorphisms might present an extremely complex pharmacologic dilemma because of the combination of very young age and genetic variability.23 In older adults, the combined effects of old age and disease can likewise increase the complexity of pharmacokinetic variability. Hence, special care must be taken in prescribing appropriate dosages in any situation where the predicted responses to drug therapy might be altered by one or more of the factors described.

Drug elimination occurs because of the combined effects of drug metabolism and excretion. Elimination is essential in terminating drug activity within a reasonable and predictable time frame. Various tissues and organs (especially the liver and kidneys) are involved in drug elimination, and injury or disease of these tissues can markedly alter the response to certain drugs. In cases of disease or injury, dosages must frequently be adjusted to prevent adverse side effects from altered elimination rates. Many other environmental, behavioral, and genetic factors may also alter drug metabolism and disposition, and possible variability in the patients response should always be a matter of concern when selecting the type and amount of the drug.

1. Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: part II. Clin Pharmacokinet. 2002;41:10771094. 2. Ament PW, Bertolino JG, Liszewski JL. Clinically significant drug interactions. Am Fam Physician. 2000; 61:17451754.

3. Attar M, Lee VH. Pharmacogenomic considerations in drug delivery. Pharmacogenomics. 2003;4:443461. 4. Bressler R, Bahl JJ. Principles of drug therapy for the elderly patient. Mayo Clin Proc. 2003;78: 15641577. 5. Buratti S, Lavine JE. Drugs and the liver: advances in metabolism, toxicity, and therapeutics. Curr Opin Pediatr. 2002;14:601607.


SECTION 1 General Principles of Pharmacology 26. Leibovitch ER, Deamer RL, Sanderson LA. Fooddrug interactions: careful drug selection and patient counseling can reduce the risk in older patients. Geriatrics. 2004;59:1922, 3233. 27. Lewis DF. 57 varieties: the human cytochromes P450. Pharmacogenomics. 2004;5:305318. 28. Long A, Walker JD. Quantitative structureactivity relationships for predicting metabolism and modeling cytochrome p450 enzyme activities. Environ Toxicol Chem. 2003;22:18941899. 29. Ma MK, Woo MH, McLeod HL. Genetic basis of drug metabolism. Am J Health Syst Pharm. 2002; 59:20612069. 30. Maka DA, Murphy LK. Drugnutrient interactions: a review. AACN Clin Issues. 2000;11:580589. 31. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2004;57:614. 32. Marzolini C, Tirona RG, Kim RB. Pharmacogenomics of the OATP and OAT families. Pharmacogenomics. 2004;5:273282. 33. Masereeuw R, Russel FG. Mechanisms and clinical implications of renal drug excretion. Drug Metab Rev. 2001;33:299351. 34. McCabe BJ. Prevention of food-drug interactions with special emphasis on older adults. Curr Opin Clin Nutr Metab Care. 2004;7:2126. 35. Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics? Clin Pharmacokinet. 2002;41:329342. 36. Neudeck BL, Foster DR, Li LY, et al. The effects of thermal injury on transcellular permeability and intestinal P glycoprotein in rats. Burns. 2003;29: 803809. 37. Noble RE. Drug therapy in the elderly. Metabolism. 2003;52(suppl 2):2730. 38. Obach RS. The prediction of human clearance from hepatic microsomal metabolism data. Curr Opin Drug Discov Devel. 2001;4:3644. 39. Oneta CM, Lieber CS, Li J, et al. Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase. J Hepatol. 2002;36:4752. 40. Oscarson M. Pharmacogenetics of drug metabolising enzymes: importance for personalized medicine. Clin Chem Lab Med. 2003;41:573580. 41. Peng X, Yan H, You Z, et al. Effects of enteral supplementation with glutamine granules on intestinal mucosal barrier function in severe burned patients. Burns. 2004;30:135139. 42. Perri D, Ito S, Rowsell V, Shear NH. The kidneythe bodys playground for drugs: an overview of renal drug handling with selected clinical correlates. Can J Clin Pharmacol. 2003;10:1723. 43. Persky AM, Eddington ND, Derendorf H. A review of the effects of chronic exercise and physical fitness level on resting pharmacokinetics. Int J Clin Pharmacol Ther. 2003;41:504516. 44. Pichette V, Leblond FA. Drug metabolism in chronic renal failure. Curr Drug Metab. 2003;4:91103.

6. Cheymol G. Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet. 2000;39:215231. 7. Ciccone CD. Basic pharmacokinetics and the potential effect of physical therapy interventions on pharmacokinetic variables. Phys Ther. 1995;75:343351. 8. Ciccone, CD. Geriatric pharmacology. In: Guccione AA, ed. Geriatric Physical Therapy. 2nd ed. St. Louis: CV Mosby; 2000. 9. Conney AH. Induction of drug-metabolizing enzymes: a path to the discovery of multiple cytochromes P450. Annu Rev Pharmacol Toxicol. 2003;43:130. 10. Della-Giustina K, Chow G. Medications in pregnancy and lactation. Emerg Med Clin North Am. 2003;21: 585613. 11. Egger SS, Drewe J, Schlienger RG. Potential drugdrug interactions in the medication of medical patients at hospital discharge. Eur J Clin Pharmacol. 2003;58:773778. 12. Evans AM. Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Ther Drug Monit. 2000;22:131136. 13. Fuhr U. Induction of drug metabolising enzymes: pharmacokinetic and toxicological consequences in humans. Clin Pharmacokinet. 2000;38:493504. 14. Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF. Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol. 2004;44:499523. 15. Goldstein DB, Tate SK, Sisodiya SM. Pharmacogenetics goes genomic. Nat Rev Genet. 2003;4:937947. 16. Gow PJ, Ghabrial H, Smallwood RA, et al. Neonatal hepatic drug elimination. Pharmacol Toxicol. 2001; 88:315. 17. Harris RZ, Jang GR, Tsunoda S. Dietary effects on drug metabolism and transport. Clin Pharmacokinet. 2003;42:10711088. 18. Hlavica P. N-oxidative transformation of free and Nsubstituted amine functions by cytochrome P450 as means of bioactivation and detoxication.Drug Metab Rev. 2002;34:451477. 19. Huang SM, Lesko LJ. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned? J Clin Pharmacol. 2004;44:559569. 20. Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci. 2004;25:193200. 21. Ito S, Lee A. Drug excretion into breast milk overview. Adv Drug Deliv Rev. 2003;55:617627. 22. Johnson TN. The development of drug metabolising enzymes and their influence on the susceptibility to adverse drug reactions in children. Toxicology. 2003;192:3748. 23. Kapur G, Mattoo T, Aranda JV. Pharmacogenomics and renal drug disposition in the newborn. Semin Perinatol. 2004;28:132140. 24. Krishnan V, Murray P. Pharmacologic issues in the critically ill. Clin Chest Med. 2003;24:671688. 25. Lee W, Kim RB. Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol. 2004;44:137166.

Chapter 3 Pharmacokinetics II: Drug Elimination 45. Pirmohamed M, Park BK. Cytochrome P450 enzyme polymorphisms and adverse drug reactions. Toxicology. 2003;192:2332. 46. Piscitelli S. Preventing dangerous drug interactions. J Am Pharm Assoc. 2000;40(suppl 1):S44S45. 47. Rodighiero V. Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet. 1999;37:399431. 48. Schmucker DL. Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging. 2001;18:837851. 49. Schoedel KA, Tyndale RF. Induction of nicotinemetabolizing CYP2B1 by ethanol and ethanol-metabolizing CYP2E1 by nicotine: summary and implications. Biochim Biophys Acta. 2003;1619:283290. 50. Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet. 2003;42:107121. 51. Segal JL, Hayes KC, Brunnemann SR, et al. Absorption characteristics of sustained-release 4 aminopyridine (fampridine SR) in patients with chronic spinal cord injury. J Clin Pharmacol. 2000;40:402409. 52. Sheweita SA. Drug-metabolizing enzymes: mechanisms and functions. Curr Drug Metab. 2000;1: 107132. 53. Srivastava P. Drug metabolism and individualized medicine. Curr Drug Metab. 2003;4:3344. 54. Strolin Benedetti M, Baltes EL. Drug metabolism and disposition in children. Fundam Clin Pharmacol. 2003;17:281299. 55. Taylor P. Agents acting at the neuromuscular junction and autonomic ganglia. In: Hardman JG, et al, eds.



57. 58. 59. 60.


62. 63.

The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001. Tett SE, Kirkpatrick CM, Gross AS, McLachlan AJ. Principles and clinical application of assessing alterations in renal elimination pathways. Clin Pharmacokinet. 2003;42:11931211. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003;38:843853. Urso R, Blardi P, Giorgi G. A short introduction to pharmacokinetics. Eur Rev Med Pharmacol Sci. 2002;6:3344. Wright JG, Boddy AV. All half-lives are wrong, but some half-lives are useful. Clin Pharmacokinet. 2001;40:237244. Wilkinson GR. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001. Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver disease. World J Gastroenterol. 2003;9:359363. You L. Steroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes. Chem Biol Interact. 2004;147:233246. Zeeh J, Platt D. The aging liver: structural and functional changes and their consequences for drug treatment in old age. Gerontology. 2002;48:121127.

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Drug Receptors
A receptor is a component of the cell where a drug binds and initiates a chain of biochemical events.2 Most drugs exert their effect by binding to and activating such a receptor, which brings about some change in the physiologic function of the cell. These receptors can be any cellular macromolecule, but many receptors have been identified as proteins or protein complexes that are located on or within the cell.45,57 The general mechanisms of receptor function, in conjunction with their cellular location, are discussed here. Perhaps the most well-known example is the acetylcholine receptor located on the postsynaptic membrane of the neuromuscular junction49,56 (Fig. 41). When bound by acetylcholine molecules, the receptor activates and opens a pore through the cell membrane, thereby increasing the permeability of the muscle cell to sodium.38,56 This action results in depolarization and excitation of the cell because of sodium influx. Another important example of a receptorion channel system is the gamma-aminobutyric acid (GABA)benzodiazepinechloride ion channel complex found on neuronal membranes in the central nervous sysNa+ ACh
(From Bourne, HR and von Zastrow, M. Drug receptors and pharmacodynamics. In: Katzung, BG ed. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw-Hill; 2004:21, with permission.)

Receptors Located on the Cells Surface

The principle site for receptors that recognize endogenous and exogenous compounds is the outer surface of the cell membrane.2 By placing receptors on its outer surface, the cell is able to differentiate and respond to specific substances that approach the cell, without actually allowing these substances to enter. These surface receptors are primarily responsive to specific amino acid, peptide, or amine compounds. Surface receptors can affect cell function (1) by acting as an ion channel and directly altering membrane permeability, (2) by acting enzymatically to directly influence function within the cell, or (3) by being linked to regulatory proteins that control other chemical and enzymatic processes within the cell. Each of the three basic ways that surface receptors can affect cell function is addressed here.




Surface Receptors Linked Directly to Ion Channels

Membrane receptors may be involved directly in the cellular response to the drug by acting as an ion pore and thus changing the membrane permeability.61

FIGURE 41 Schematic model of the acetylcholine receptor, an example of a surface receptor that is linked directly to an ion channel. Binding of two acetylcholine (ACh) molecules to the outer surface of the receptor protein induces the opening of a central ion channel, thus allowing sodium to enter the cell.



SECTION 1 General Principles of Pharmacology

tem.46,51 In this situation, the membranes permeability to chloride is increased by the binding of both the neurotransmitter GABA and benzodiazepine drugs such as diazepam (Valium) and chlordiazepoxide (Librium). The function of this chloride ion channel complex is discussed in more detail in Chapter 6. Surface receptors for other substancessuch as ions (sodium, potassium, calcium) and amino acids (glutamate) have been identified, and are likewise linked directly to ion channels that control permeability of the cell membrane.37,61

Surface Receptors Linked Directly to Enzymes

Some proteins that span the entire width of the cell membrane may have an extracellular receptor site (binding domain) as well as an intracellular enzymatic component (catalytic domain)21,44 (Fig. 42). Drugs and endogenous chemicals that bind to the receptor site can change the enzyme activity of the intracellular catalytic component, thus altering the biochemical function within the cell.43Receptor-enzyme systems in this category are often referred to as protein tyrosine kinases because binding of an appropriate substance to the outer (receptor) component initiates the phosphorylation of certain tyrosine amino acids on the inner (catalytic) component of the protein, which in turn A.

increases the enzyme activity of the intracellular component (see Fig. 42).22,43 The activated enzymatic component of the receptor then catalyzes the activation of other substrates within the cell. It appears that insulin and certain growth factors may exert their effects by acting through this type of tyrosine kinase receptor-enzyme system.21,44 Insulin, for example, binds to the extracellular component of a protein located on skeletal muscle cells, thereby initiating activation of this proteins enzymatic activity on the inner surface of the cell membrane. This change in enzyme function causes further changes in cell activity, which ultimately result in increased glucose uptake in the muscle cell. The function of insulin receptors and their role in the cause and treatment of diabetes mellitus are discussed in more detail in Chapter 32.

Surface Receptors Linked to Regulatory (G) Proteins: Role of the Second Messenger
Rather than directly affecting membrane permeability or directly influencing enzyme activity, other membrane receptors affect cell function by linking to an intermediate regulatory protein that is located on the inner surface of the cells membrane.2,23,45 These regulatory proteins are activated by binding guanine B.

Agonist Molecules


In. P P


Substrate (inactive)

Substrate (active)

FIGURE 42 Example of a surface receptor that is linked directly to intracellular enzyme activity. (A) The receptor exists in an inactive state as two subunits: each subunit has a binding domain (BD) on the outer surface and a catalytic domain (CD) on the inner surface. (B) Binding of agonist molecules to the BDs causes the subunits to join together and induces phosphorylation (P) of tyrosine receptors on the CD. Tyrosine phosphorylation initiates enzymatic activity of the catalytic units, which then causes substrate activation within the cell.

Chapter 4 Drug Receptors


nucleotides; hence they are often termed G proteins.2 When an appropriate substance binds to the surface receptor, the receptor moves laterally in the cell membrane, and attaches to the regulatory G protein.24 This attachment activates the G protein, which in turn alters the activity of a type of intracellular effector (such as an enzyme or ion channel), ultimately leading to a change in cell function.27,59 Receptors that are linked to G proteins (also called G proteincoupled receptors) represent the primary way that signals from the surface receptor are transduced into the appropriate response within the cell.2,23 There appear to be two types of regulatory G proteins: a stimulatory protein (Gs), which increases the cellular response, and an inhibitory protein (Gi), which decreases that response (Fig. 43). The two types of G proteins are linked to two different receptors that are responsive to different drugs. Certain drugs affect the cell by binding to a receptor that is linked to a Gs protein. The activated receptor activates the Gs protein, which in turn activates the effector system that opens an ion channel or activates a specific enzyme. Conversely, a drug that binds to a receptor that is linked to a Gi protein, inhibits channel opening or intracellular enzyme activity. Hence, regulatory G proteins help account for how drugs can bind to one type of receptor and stimulate cell function, whereas drugs that bind to a different receptor on the same cell can inhibit cell activity. G proteins also seem to be important in mediating the other cell responses to stimulation or inhibition. For instance, cell function may continue to be

R1 Gs Adenylate Cyclase Gi


ATP cyclic AMP protein kinase (inactive) protein kinase (active)

FIGURE 43 Schematic diagram of a surface receptorsecond messenger system. In this example, the second messenger is cAMP, which is synthesized from ATP by the adenylate cyclase enzyme. The enzyme is linked to surface receptors (R1 and R2) by regulatory G proteins. GS stimulates the enzyme and Gi inhibits enzyme activity. Thus, a drug binding to R1 will increase production of cAMP, while a different drug binding to R2 will inhibit cAMP production.

affected through the action of G proteins even after the drug has left the binding site on the cells surface2; that is, the drug may bind to the cell for only a short period, but this binding is sufficient to initiate the interaction of the G protein with the intracellular effector system. Sustained influence of the G protein on the effector system helps explain why the cell may continue to exhibit a response even after the drug has dissociated from it, or even after the drug has been eliminated from the body completely. As indicated earlier, many G proteincoupled receptors are linked directly to an intracellular enzyme. Drugs and other substances that exert their effects through receptorG proteinenzyme systems often form (or inhibit the formation of) an intracellular compound known as a second messenger. In effect, the drug acts as the first messenger, which triggers a biochemical change in the cell, but the drug itself does not enter. The second messenger, which is the substance produced inside the cell, actually mediates the change in function. The primary example of this type of second messenger strategy is the adenylate cyclasecyclic adenosine monophosphate (cAMP) system present in many cells (see Fig. 43).50,53 Adenylate cyclase, an enzyme that is located on the inner surface of the cell membrane, is responsible for hydrolyzing adenosine triphosphate (ATP) into cAMP. Cyclic AMP acts as the second messenger in this system by activating other enzymes (i.e., protein kinases) throughout the cell. Thus, drugs that bind to a surface receptor that is linked to a Gs protein will increase adenylate cyclase activity, resulting in increased production of cAMP within the cell. Other drugs bound to a different receptor that is linked to a Gi protein will inhibit adenylate cyclase activity, resulting in decreased production of cAMP. The adenylate cyclasecAMP system is associated with specific membrane receptors such as the betaadrenergic receptors.20 Other surface receptors may also be linked to this particular effectorsecond messenger system, or they may be linked to other intracellular processes that use different second messengers including: cyclic guanine monophosphate (cGMP), cyclic adenosine diphosphoribose (cADPR), diacylglycerol, phosphoinositides, nicotinic acid adenine dinucleotide phosphate (NAADP), and calcium ions.11,17,28,34,39,42,47,48 Finally, alterations in the synthesis, function, and regulation of G proteins have been identified in certain pathologic conditions, including alcoholism, diabetes mellitus, heart failure, and certain tumors.20.26,35,41,52,60


SECTION 1 General Principles of Pharmacology

This illustrates the fact that G proteins seem to play an integral role in mediating the cells response to various substances in both normal and disease states. The importance of these regulatory proteins will almost certainly continue to emerge as additional information about their structure and function becomes available.

Intracellular Receptors
Receptors have been identified at intracellular locations such as the cytoplasm and the nucleus.1,4,10 These intracellular receptors are specific for certain endogenous hormones, and the drugs that affect them. For instance, steroid and steroidlike compounds exert some of their effects by initially interacting with a receptor that is located in the cytoplasm.4,6,31 Specifically, these hormones form a complex with the receptor in the cytoplasm, and the hormone-receptor complex then moves to the cells nucleus, where it affects the function of specific genes. Thyroid hormones (thyroxin, triiodothyronine) appear to bind directly to a receptor located on the chromatin in the cells nucleus.18 In either case, cell function is altered because the hormone-receptor complex affects specific genes in the DNA and causes changes in gene expression and messenger RNA transcription. Altered transcription of specific genes results in altered cellular protein synthesis, which ultimately results in altered cell function.1 Hence, certain endogenous hormones and hormone-like drugs exert some of their effects by acting on receptors located within the cell. It has become clear, however, that these substances might also exert some of their effects by binding to a second set of receptors located on the cell surface.10,18 That is, surface receptors have been identified for steroid and thyroid hormones, and stimulation of these surface receptors might compliment or exaggerate the effects of the intracellular receptors.1,31 The role of intracellular receptors, and their analogous surface receptors, is discussed further in this text in the chapters that deal with specific drugs that bind to these cellular components.

Drug-Receptor Interactions
The ability a drug has to bind to any receptor is dictated by factors such as the drugs size and shape relative to the configuration of the binding site on the receptor. The electrostatic attraction between the drug

and the receptor may also be important in determining the extent to which the drug binds to the receptor. This drug-receptor interaction is somewhat analogous to a key fitting into a lock. The drug acts as a key that will only fit into certain receptors. Once inserted into a suitable receptor, the drug activates the receptor, much like a key turning and activating the appropriate lock. To carry this analogy one step further, unlocking a door to a room would increase the permeability of the room in a manner similar to the direct effect of certain activated membrane receptors (e.g., the acetylcholine receptor on the neuromuscular junction). Other types of key-lock interactions would be linked to some other event, such as using a key to start an automobile engine. This situation is analogous to linking a surface receptor to some intracellular enzymatic process that would affect the internal machinery of the cell. Although key-lock analogy serves as a crude example of drug-receptor interactions, the attraction between a drug and any receptor is much more complex. Binding a drug to a receptor is not an all-or-none phenomenon, but is graded depending on the drug in question. Some drugs will bind readily to the receptor, some moderately, some very little, or some not at all. The term affinity is used to describe the amount of attraction between a drug and a receptor.45 Affinity is actually related to the drug amount that is required to bind to the unoccupied receptors.25 A drug with a high affinity binds readily to the open receptors, even if the concentration of the drug is relatively low. Drugs with moderate or low affinity require a higher concentration in the body before the receptors become occupied. In addition to the relative degree of affinity of different drugs for a receptor, apparently the status of the receptor may also vary under specific conditions. Receptors may exist in variable affinity states (superhigh, high, low) depending on the influence of local regulators such as guanine nucleotides, ammonium ions, and divalent cations.45 These local regulators are also known as allosteric modulators, which can bind to specific sites on the receptor that are distinct from the primary (drug) binding site, and thereby increase or decrease the affinity for the drug.23,36 Membrane receptors may also be influenced by the local environment of the lipid bilayer. The amount of flexibility or fluidity of the cell membrane is recognized as being critical in providing a suitable environment in which membrane constituents such as receptors can optimally function. Physical and chemical factors (including other drugs) may change the fluidity and organization of the membrane, thereby disrupting the normal ori-

Chapter 4 Drug Receptors


entation of the receptor and subsequently altering its affinity state and ability to interact with a drug.9,29 The exact way in which a drug activates a receptor has been the subject of considerable debate. Binding a drug to the receptor is hypothesized to cause the receptor to undergo some sort of temporary change in its shape or conformation. The change in structure of the activated receptor then mediates a change in cell function, either directly or by linking to some effector system. Studies have suggested that certain receptor proteins, such as the acetylcholine receptor, undergo a specific change in structure after binding with specific chemicals.38, 55, 56 This event certainly seems plausible because most receptors have been identified as protein molecules, and proteins are known to be able to reversibly change their shape and conformation as part of normal physiologic function.45 This fact should not, however, rule out other possible ways in which an activated receptor may mediate changes in cell function. Future research will continue to clarify the role of conformational changes as well as other possible mechanisms of receptor activation.

Drug Selectivity and Receptor Subtypes

A drug is said to be selective if it affects only one type of cell or tissue and produces a specific physiologic response. For instance, a drug that is cardioselective will affect heart function without affecting other tissues such as the gastrointestinal tract or respiratory system. The selectivity of a particular drug is a function of the drugs ability to interact with specific receptors on the target tissue, and not with other receptors on the target tissue or on other tissues (Fig. 44). In reality, drug selectivity is a relative term because no drug produces only one effect. Drugs can be compared with one another, however, with the more selective drug being able to affect one type of tissue or organ with only a minimum of other responses. The issue of drug selectivity is related closely to the fact that many receptor populations can be divided into various subtypes according to specific structural and functional differences between subgroups of the receptor. A primary example is the cholinergic (acetylcholine) receptor found on various tissues throughout the body. These receptors can be classified into two primary subtypes: muscarinic and nicotinic. Acetylcholine will bind to either subtype, but drugs such as nicotine will bind preferentially to the nicotinic subtype, and muscarine (a toxin found in certain mushrooms) will bind preferentially to the muscarinic subtype.

Functional Aspects of Drug-Receptor Interactions

The interaction between the drug and the receptor dictates several important aspects of pharmacology, including those discussed here.

Selective Drug

Nonselective Drug

Primary (beneficial) Effect TISSUE "A"

Side Effect


FIGURE 44 Drug selectivity. The diagram represents an ideal situation where the selective drug produces only beneficial effects and the nonselective drug exerts both beneficial and nonbeneficial effects. Drug selectivity is actually a relative term, because all drugs produce some side effects; however, a selective drug produces fewer side effects than a nonselective agent.


SECTION 1 General Principles of Pharmacology

Other types of receptors can be divided and subdivided in a similar manner. For example, the adrenergic receptor (i.e., the receptor for epinephrine or adrenaline) is divided into two primary subtypes (alpha and beta), with each subtype having two primary divisions (alpha-1 and alpha-2; beta-1 and beta-2). Epinephrine will stimulate all adrenergic receptor subtypes, but certain drugs will only affect one of the primary divisions (e.g., a beta-selective drug), or even one subtype within each division (e.g., a beta-1 selective drug). The functional significance of adrenergic and cholinergic receptors is discussed in more detail in Chapter 18. Receptor subtypes also exist for other substances (opioids, dopamine, GABA, hormones, and so forth); the significance of these will be addressed in their respective chapters in this text. The fact that many receptors can be classified into subtypes presents the opportunity to develop drugs that will produce fairly selective effects because they affect only one receptor subtype.5,16 A beta-1 selective drug, for example, will primarily affect the heart because the heart basically contains the beta-1 subtype of adrenergic receptor, while other tissues (lungs, arterioles) contain other subtypes of adrenergic receptors. Research is ongoing to learn more about the structure and function of receptor populations and their subtypes. By knowing the characteristics of a specific receptor subtype, drugs can be designed to affect only that subtype and therefore will produce more selective effects with fewer side effects.5,13

occupies half the available receptors, for example, may produce a response that is greater than 50 percent of the maximal response.25 Clearly, other factors influence the absolute magnitude of the response, including factors that influence the relative affinity for the drug, and how well the occupied receptor can transmit the signal to the cells effector mechanisms. It is, nonetheless, essentially true that increasing or decreasing the amount of drug available to the appropriate receptors will bring about a concomitant increase or decrease in the response to that drug.45

Classification of Drugs: Agonist Versus Antagonist

So far, drug-receptor interactions have been used to describe the process by which a drug occupies a receptor and in some way activates it. The activated receptor then brings about a change in cell function. A drug that can bind to a receptor and initiate a change in the function of the cell is referred to as an agonist. An agonist is identified as having affinity and efficacy.2,45 As discussed earlier, affinity refers to the fact that there is an attraction, or desire, for the drug to bind to a given receptor. The second characteristic, efficacy, indicates that the drug will activate the receptor and will subsequently lead to a change in the function of the cell. Whereas an agonist has both affinity and efficacy, an antagonist has only affinity. This means that the drug will bind to the receptor, but it will not cause any direct change in the function of the receptor or cell (Fig. 45). Antagonists are significant because, by occupying the receptor, they prevent the agonistic compound from having any effect on the cell. Antagonists are often referred to as blockers because of their ability to block the effect of another chemical. The primary pharmacologic significance of these antagonists has been their use in blocking the effects of certain endogenous compounds. A classic example of this is the use of the so-called beta blockers, which occupy specific receptors on the myocardium, thus preventing circulating catecholamines from increasing heart rate and contractility. Other examples of antagonistic drugs are discussed in their appropriate chapters.

The shape of the typical dose-response curve discussed in Chapter 1 is related to the number of receptors that are bound by the drug (see Fig. 12), because within certain limits of the drug concentration, the response is essentially proportional to the number of receptors occupied by the drug.2,25 At low dosages, for example, only a few receptors are bound by the drug; hence, the effect is relatively small. As the dosage (and drug concentration) increases, more receptors become occupied and the response increases. Finally, at a certain dosage, all available receptors will be occupied, and the response will be maximal. Increasing the dosage beyond the point at which the maximal effect is reached will not produce any further increase in response because all the receptors are bound by the drug. It should be noted, however, that the relationship between drug receptors and drug response is not a simple linear relationship for many drugs. A drug that

Competitive Versus Noncompetitive Antagonists

Pharmacologic antagonists are generally divided into two categories depending on whether they are com-

Chapter 4 Drug Receptors









Physiologic Effect
FIGURE 45 Drug classification: agonist versus antagonist. The antagonist (blocker) prevents the agonist from binding to the receptor and exerting a physiologic effect.

peting with the agonist for the receptor.2,45 Competitive antagonists are so classified because they seem to be vying for the same receptor as the agonist. In other words, both the agonist and antagonist have an equal opportunity to occupy the receptor. For practical purposes, whichever drug concentration is greater tends to have the predominant effect. If the number of competitive antagonist molecules far exceeds the number of agonist molecules, the antagonists will occupy most of the receptors and the overall effect will be inhibition of the particular response. Conversely, a high concentration of an agonist relative to an antagonist will produce a pharmacologic effect, because the agonist will occupy most of the receptors. In fact, raising the concentration of the agonist with a competitive antagonist present can actually overcome the original inhibition, because the competitive antagonists form rather weak bonds with the receptor and can be displaced from it by a sufficient concentration of agonist molecules.2,45 This is an important advantage of competitive antagonists because, if necessary, the inhibition caused by the antagonist can be overcome simply by administering high concentrations of the agonist. In contrast to competitive antagonists, noncompetitive antagonists form strong, essentially permanent, bonds to the receptor. Noncompetitive antagonists either have an extremely high affinity for the receptor or actually form irreversible covalent bonds to the receptor.2,45 Once bound to the receptor, the noncom-

petitive antagonist cannot be displaced by the agonist, regardless of how much agonist is present. Thus the term noncompetitive refers to the inability of the agonist to compete with the antagonist for the receptor site. The obvious disadvantage to this type of receptor blocker is that the inhibition cannot be overcome in cases of an overdose of the antagonist. Also, noncompetitive antagonists often remain bound for the receptors lifespan, and their effect is terminated only after the receptor has been replaced as part of the normal protein turnover within the cell. Consequently, the inhibition produced by a noncompetitive blocker tends to remain in effect for long periods (i.e., several days).

Partial Agonists
Drugs are classified as partial agonists when they do not evoke a maximal response compared to a strong agonist. This classification is used even though the partial agonist occupies all available receptors.3,32 In fact, partial agonists can be thought of as having an efficacy that lies somewhere between that of a full agonist and a full noncompetitive antagonist. The lack of a maximal response is not caused by decreased drug-receptor affinity. On the contrary, partial agonists often have a high affinity for the receptor. The decreased efficacy may be caused by the fact that the partial agonist does not completely activate the receptor after it binds, and that binding results in a lower level of any postrecep-


SECTION 1 General Principles of Pharmacology

tor events (e.g., less activation of G proteins, smaller changes in enzyme function). Hence, the realization that certain drugs act as partial agonists has led to the idea that a range of efficacy can exist, depending on how specific drugs interact with their respective receptors.3 At one end of this range are the drugs that bind strongly and produce a high degree of efficacy (strong agonists), while the other end of the spectrum contains drugs that bind strongly and produce no effect (strong antagonists). Agents that fall between these two extremes (partial agonists) can have varying degrees of agonistic activity. These partial agonists can also have certain clinical advantages. For instance, certain antipsychotic drugs that function as partial agonists may reduce psychotic episodes without excessive side effects.15,32 Other examples of how partial agonists can be used clinically are discussed elsewhere in this text.

ity in situations where the receptor is too active or overstimulated.25 Future studies will be needed to determine to what extent inverse agonists might be useful as therapeutic agents.

Receptor Regulation
Receptor responses are not static but are regulated by endogenous and exogenous factors. In general, a prolonged increase in the stimulation of various receptors will lead to a decrease in receptor function, and decreased stimulation will lead to an increase in receptor numbers or sensitivity (Fig. 46). The mechanisms and significance of these receptor changes are described here.

Mixed AgonistAntagonists and Inverse Agonists

Some agents will stimulate certain receptor subtypes, while simultaneously blocking the effects of endogenous substances on other receptor subtypes (the concept of receptor subtypes was addressed earlier in this chapter). These agents are known as mixed agonistantagonists, and they are especially useful in certain clinical situations.2 In some women, for example, it is often beneficial to stimulate estrogen receptors on bone to prevent osteoporosis, while simultaneously blocking the effects of estrogen on breast tissues to prevent cancer. Hence, certain drugs known as selective estrogen receptor modulators (SERMs; see Chapters 30, 31, and 36) can differentiate between the subtypes of estrogen receptors on these two tissues, and act as an agonist on bone and an antagonist on breast tissues.19 These agents are a good example of drugs with mixed agonistantagonist activity, and other drugs with this type of mixed activity will be discussed in their respective chapters throughout this text. Finally, it has been proposed that some drugs could function as inverse agonists.3,25 As this classification implies, these drugs would bind to the same receptor as the agonist, but have the opposite effect on cellular function compared to the agonist. This effect is different from a traditional, or neutral, antagonist that binds to the tissue and simply prevents an increase in the agonists effect. By creating the opposite effect, inverse agonists could bring about a decrease in activ-

Receptor Desensitization and Down-Regulation

As presented in Figure 46, overstimulation of postsynaptic receptors by endogenous substances (neurotransmitters, hormones) or by exogenous agonists (drugs) may lead to a functional decrease in the appropriate receptor population.54,58 In effect, the cell becomes less responsive to the prolonged stimulation by decreasing the number of active receptors. The term desensitization is used to describe a fairly brief and transient decrease in responsiveness.2,8 Desensitization is believed to occur because of the addition of phosphate residues (phosphorylation) or some other chemical modification to the receptor protein.25,33 Adding a phosphate molecule seems to cause some membrane receptors to be uncoupled from their intermediate regulatory proteins and consequently from the rest of the cells biochemical machinery.40 Receptor desensitization helps account for the decrease in response that may be seen even though the agonist remains present in high concentration in the body. The decrease in responsiveness caused by desensitization is fairly brief, however, and a return to normal response may occur within a few minutes after the agonist is removed. Receptor down-regulation describes a slower, more prolonged process in which the actual number of available receptors is diminished.30,33 Although the exact mechanisms responsible for down-regulation are not fully understood, it appears that prolonged exposure of the agonist causes increased receptor removal, decreased receptor synthesis, or a combination of

Chapter 4 Drug Receptors


Presynaptic Terminal

Postsynaptic Terminal

Normal Synapse

Increased Stimulation

Decreased Stimulation

Receptor Desensitization/ Down-regulation

Receptor Supersensitivity

FIGURE 46 Receptor regulation. Functionally active receptor sites are represented by an X. Increased stimulation results in a decrease in receptor numbers (desensitization/down-regulation), while decreased stimulation causes increased receptor numbers (supersensitivity).

increased removal and decreased synthesis.40 In any event, the cell undergoes a decrease in responsiveness that remains in effect long after the agonist is removed (i.e., several days). Normal sensitivity to the agonist will be reestablished only when the cell has had the chance to replace and restore the receptors that were eliminated during downregulation. Receptor desensitization and down-regulation appear to be examples of a negative feedback system used by the cell to prevent overstimulation by an agonist. The cell appears to selectively decrease its responsiveness to a particular stimulus in order to protect itself from excessive perturbation. Receptor down-regulation is important pharmacologically because it may be one of the primary reasons that a decrease in drug responsiveness occurs when certain drugs are used for prolonged periods.33 Likewise, receptor desensitization and downregulation have been linked to several pathological situations, and drugs that prevent these decreases in receptor function could prove useful in conditions such as acute CNS injury, cardiac disease, or HIV infection.8,12,30 Conversely, some drugs, such as the antidepressants, may exert their beneficial effects by intentionally causing receptor down-regulation and desensitization in certain neural pathways that cause

clinical depression. These drugs are discussed in detail in Chapter 7.

Receptor Supersensitivity
A prolonged decrease in the stimulation of the postsynaptic receptors can result in a functional increase in receptor sensitivity. The best example of this is the denervation supersensitivity seen when a peripheral nerve is severed.7 In this situation, the lack of presynaptic neurotransmitter release results in a compensatory increase in postsynaptic receptor numbers on the muscle cell. Similarly, the loss of the endogenous neurotransmitter dopamine in neurodegenerative conditions such as Parkinson disease can result in supersensitivity of receptors for that neurotransmitter.14 This increased receptor sensitivity becomes problematic because administration of dopaminelike drugs can cause excessive or untoward responses (see Chapter 10).14 A somewhat different type of denervation supersensitivity can also occur when receptor antagonist drugs are used for prolonged periods. Here the postsynaptic receptors are blocked by the antagonistic drug, and are unavailable for stimulation by the appropriate agonist. The postsynaptic neuron interprets this


SECTION 1 General Principles of Pharmacology

as if the synapse were denervated and responds by manufacturing more receptors, resulting in a compensatory increase in function at the synapse that was supposed to be blocked by the antagonist. Again, drug therapy could be affected in this situation because the dose of the blocker will need to be altered to cope with the new, larger population of receptors.

Many drugs and endogenous chemicals exert their effects by first binding to and activating a cellular receptor. Cellular receptors seem to be proteins located on the cell surface or at specific locations within the cell. The primary role of the receptor is to recognize specific chemicals from the vast number of compounds that are introduced to the cell and to initiate a change in cell function by interacting with a specific agent. Activated receptors mediate a change in function by altering cell permeability or modifying the biochemical function within the cell, or both. The exact mechanism by which a receptor affects cell function depends on the type and location of the receptor. Drug-receptor interactions are significant pharmacologically because they account for some of the basic pharmacodynamic principles such as drug selectivity and the relationship between drug dose and response. Also, the development of chemical agents that block specific receptors (antagonists) has been useful in moderating the effects of endogenous compounds on specific physiologic processes. Finally, changes in receptor number and sensitivity have been implicated as being important in the altered response seen in certain drugs with prolonged use. Information about the relationship between drugs and cellular receptors has been, and will continue to be, critical to our understanding of how drugs work, as well as to helping researchers develop new compounds.

Nonreceptor Drug Mechanisms

Certain drugs do not appear to exert their effects by binding to a specific cellular component.45 For example, certain cancer chemotherapeutic agents act as antimetabolites by becoming incorporated into the manufacture of specific cellular components. The drug acts as an improper ingredient in the biosynthesis of the component, so that the cell does not manufacture harmful or unwanted materials. In addition, many common antacids work by directly neutralizing stomach acid; that is, these drugs act via a chemical reaction rather than through a specific receptor molecule. Other drugs may affect cell function without first binding to a receptor by directly altering enzyme function or by acting as chelating agents, which bind to harmful compounds such as heavy metals and prevent them from exerting toxic effects. Additional nonreceptormediated mechanisms of specific compounds are discussed when those drugs are examined in their respective chapters.

1. Bassett JH, Harvey CB, Williams GR. Mechanisms of thyroid hormone receptorspecific nuclear and extra nuclear actions. Mol Cell Endocrinol. 2003;213:111. 2. Bourne HR, von Zastrow M. Drug receptors and pharmacodynamics. In: Katzung, BG, ed. Basic and Clinical Pharmacology., 9th ed. New York: Lange Medical Books/McGraw-Hill; 2004. 3. Brink CB, Harvey BH, Bodenstein J, et al. Recent advances in drug action and therapeutics: relevance of novel concepts in G-proteincoupled receptor and signal transduction pharmacology. Br J Clin Pharmacol. 2004;57:373387. 4. Buckbinder L, Robinson RP. The glucocorticoid receptor: molecular mechanism and new therapeutic opportunities. Curr Drug Targets Inflamm Allergy. 2002;1:127136. 5. Bunnelle WH, Dart MJ, Schrimpf MR. Design of ligands for the nicotinic acetylcholine receptors:

the quest for selectivity. Curr Top Med hem. 2004; 4:299334. 6. Carlberg C. Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands. Recent Results Cancer Res. 2003;164:2942. 7. Csillik B, Nemcsok J, Chase B, et al. Infraterminal spreading and extrajunctional expression of nicotinic acetylcholine receptors in denervated rat skeletal muscle. Exp Brain Res. 1999;125:426434. 8. El-Armouche A, Zolk O, Rau T, Eschenhagen T. Inhibitory G-proteins and their role in desensitization of the adenylyl cyclase pathway in heart failure. Cardiovasc Res. 2003;60:478487. 9. Elmendorf JS. Fluidity of insulin action. Mol Biotechnol. 2004;27:127138. 10. Farach-Carson MC, Davis PJ. Steroid hormone interactions with target cells: cross talk between membrane and nuclear pathways. J Pharmacol Exp Ther. 2003; 307:839845.

Chapter 4 Drug Receptors 11. Feil R, Lohmann SM, de Jonge H, et al. Cyclic GMP dependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res. 2003;93:907916. 12. Frandsen A, Schousboe A. AMPA receptormediated neurotoxicity: role of Ca2 and desensitization. Neurochem Res. 2003;28:14951499. 13. Gentilucci L. New trends in the development of opioid peptide analogues as advanced remedies for pain relief. Curr Top Med Chem. 2004;4:1938. 14. Gerfen CR. D1 dopamine receptor supersensitivity in the dopamine depleted striatum animal model of Parkinsons disease. Neuroscientist. 2003;9:455462. 15. Grunder G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry. 2003;60: 974977. 16. Grutter T, Le Novere N, Changeux JP. Rational understanding of nicotinic receptors drug binding. Curr Top Med Chem. 2004;4:645650. 17. Guse AH. Regulation of calcium signaling by the second messenger cyclic adenosine diphosphoribose (cADPR). Curr Mol Med. 2004;4:239248. 18. Harvey CB, Williams GR. Mechanism of thyroid hormone action. Thyroid. 2002;12:441446. 19. Haskell SG. Selective estrogen receptor modulators. South Med J. 2003;96:469476. 20. Hata JA, Koch WJ. Phosphorylation of G protein coupled receptors: GPCR kinases in heart disease. Mol Interv. 2003;3:264272. 21. Hawkes C, Kar S. The insulin-like growth factor-II/ mannose-6-phosphate receptor: structure, distribution and function in the central nervous system. Brain Res Brain Res Rev. 2004;44:117140. 22. Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annu Rev Biochem. 2000; 69:373398. 23. Jensen AA, Spalding TA. Allosteric modulation of G-protein coupled receptors. Eur J Pharm Sci. 2004; 21:407420. 24. Kenakin T. Drug efficacy at G proteincoupled receptors. Annu Rev Pharmacol Toxicol. 2002;42:349379. 25. Kenakin T. Principles: receptor theory in pharmacology. Trends Pharmacol Sci. 2004;25:186192. 26. Kowluru A, Morgan NG. GTP-binding proteins in cell survival and demise: the emerging picture in the pancreatic beta-cell. Biochem Pharmacol. 2002;63: 10271035. 27. Kowluru A. Regulatory roles for small G proteins in the pancreatic beta cell: lessons from models of impaired insulin secretion. Am J Physiol Endocrinol Metab. 2003;285:E669E684. 28. Kuhn M. Structure, regulation, and function of mammalian membrane guanylyl cyclase receptors, with a focus on guanylyl cyclase-A. Circ Res. 2003; 93:700709. 29. Leifert WR, Jahangiri A, McMurchie EJ. Membrane fluidity changes are associated with the antiarrhythmic effects of docosahexaenoic acid in adult rat cardiomyocytes. J Nutr Biochem. 2000;11:3844.


30. Levesque K, Finzi A, Binette J, Cohen EA. Role of CD4 receptor down regulation during HIV-1 infection. Curr HIV Res. 2004;2:5159. 31. Levin ER. Cell localization, physiology, and nongenomic actions of estrogen receptors. J Appl Physiol. 2001;91:18601867. 32. Lieberman JA. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs. 2004;18:251267. 33. Liu-Chen LY. Agonist-induced regulation and trafficking of kappa opioid receptors. Life Sci. 2004;75: 511536. 34. Macrez N, Mironneau J. Local Ca2 signals in cellular signalling. Curr Mol Med. 2004;4:263275. 35. Mailliard WS, Diamond I. Recent advances in the neurobiology of alcoholism: the role of adenosine. Pharmacol Ther. 2004;101:3946. 36. May LT, Christopoulos A. Allosteric modulators of G-proteincoupled receptors. Curr Opin Pharmacol. 2003;3:551556. 37. McFeeters RL, Oswald RE. Emerging structural explanations of ionotropic glutamate receptor function. FASEB J. 2004;18:428438. 38. Miyazawa A, Fujiyoshi Y, Unwin N. Structure and gating mechanism of the acetylcholine receptor pore. Nature. 2003;423:949955. 39. Newton AC. Diacylglycerols affair with protein kinase C turns 25. Trends Pharmacol Sci. 2004;25:175177. 40. Ossovskaya VS, Bunnett NW. Protease-activated receptors: contribution to physiology and disease. Physiol Rev. 2004;84:579621. 41. Petrofski JA, Koch WJ. The beta-adrenergic receptor kinase in heart failure. J Mol Cell Cardiol. 2003;35: 11671174. 42. Pilz RB, Casteel DE. Regulation of gene expression by cyclic GMP. Circ Res. 2003;93:10341046. 43. Romano G. The complex biology of the receptor for the insulin-like growth factor-1. Drug News Perspect. 2003;16:525531. 44. Roskoski R Jr. The ErbB/HER receptor protein tyrosine kinases and cancer. Biochem Biophys Res Commun. 2004;319:111. 45. Ross EM, Kenakin,TP. Pharmacodynamics: mechanisms of drug action and the relationship between drug concentration and effect. In: Hardman, JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 46. Rudolph U, Mohler H. Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol. 2004;44:475498. 47. Schulz I, Krause E. Inositol 1,4,5-trisphosphate and its co-players in the concert of Ca2 signallingnew faces in the line up. Curr Mol Med. 2004;4:313322. 48. Shisheva A. Regulating Glut4 vesicle dynamics by phosphoinositide kinases and phosphoinositide phosphatases. Front Biosci. 2003;8:s945946. 49. Sine SM. The nicotinic receptor ligand binding domain. J Neurobiol. 2002;53:431446. 50. Skalhegg BS, Tasken K. Specificity in the cAMP/ PKA signaling pathway. Differential expression,


SECTION 1 General Principles of Pharmacology regulation, and subcellular localization of subunits of PKA. Front Biosci. 2000;5:D678D693. Steiger JL, Russek SJ. GABAA receptors: building the bridge between subunit mRNAs, their promoters, and cognate transcription factors. Pharmacol Ther. 2004; 101:259281. Tan CM, Brady AE, Nickols HH, et al. Membrane trafficking of G proteincoupled receptors. Annu Rev Pharmacol Toxicol. 2004;44:559609. Tasken K, Aandahl EM. Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev. 2004;84:137167. Toews ML, Prinster SC, Schulte NA. Regulation of alpha-1B adrenergic receptor localization, trafficking, function, and stability. Life Sci. 2003;74:379389. Unwin N. Structure and action of the nicotinic acetylcholine receptor explored by electron microscopy. FEBS Lett. 2003;555:9195. 56. Unwin N, Miyazawa A, Li J, Fujiyoshi Y. Activation of the nicotinic acetylcholine receptor involves a switch in conformation of the alpha subunits. J Mol Biol. 2002;319:11651176. 57. Watson CS, Gametchu B. Proteins of multiple classes may participate in nongenomic steroid actions. Exp Biol Med (Maywood). 2003;228:12721281. 58. Woolf PJ, Linderman JJ. Untangling ligand induced activation and desensitization of G-proteincoupled receptors. Biophys J. 2003;84:313. 59. Yin D, Gavi S, Wang HY, Malbon CC. Probing receptor structure/function with chimeric G-proteincoupled receptors. Mol Pharmacol. 2004;65:13231332. 60. Yowell CW, Daaka Y. G proteincoupled receptors provide survival signals in prostate cancer. Clin Prostate Cancer. 2002;1:177181. 61. Zhorov BS, Tikhonov DB. Potassium, sodium, calcium and glutamate-gated channels: pore architecture and ligand action. J Neurochem. 2004;88:782799.


52. 53. 54.



Pharmacology of the Central Nervous System

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General Principles of Central Nervous System Pharmacology

The central nervous system (CNS) is responsible for controlling bodily functions as well as being the center for behavioral and intellectual abilities. Neurons within the CNS are organized into highly complex patterns that mediate information through synaptic interactions. CNS drugs often attempt to modify the activity of these neurons in order to treat specific disorders or to alter the general level of arousal of the CNS. This chapter presents a simplified introduction to the organization of the CNS and the general strategies that can be used with drugs to alter activity within the brain and spinal cord. and occipital). The outer cerebrum, or cerebral cortex, is the highest order of conscious function and integration in the CNS. Specific cortical areas are responsible for sensory and motor functions as well as intellectual and cognitive abilities. Other cortical areas are involved in short-term memory and speech. The cortex also operates in a somewhat supervisory capacity regarding lower brain functioning and may influence the control of other activities such as the autonomic nervous system. With regard to CNS drugs, most therapeutic medications tend to affect cortical function indirectly by first altering the function of lower brain and spinal cord structures. An exception is the group of drugs used to treat epilepsy; these drugs are often targeted directly for hyperexcitable neurons in the cerebral cortex. In addition, drugs that attempt to enhance cognitive function in conditions such as Alzheimer disease (cholinergic stimulants; see Chapter 19) might also exert their primary effects in the cerebrum.

CNS Organization
The CNS can be grossly divided into the brain and spinal cord (Fig. 51). The brain is subdivided according to anatomic or functional criteria. The following is a brief overview of the general organization of the brain and spinal cord, with some indication of where particular CNS drugs tend to exert their effects. This chapter is not intended to be an extensive review of neuroanatomya more elaborate discussion of CNS structure and function can be found in several excellent sources.25,28,40,41

Basal Ganglia
A group of specific areas located deep within the cerebral hemispheres is collectively termed the basal ganglia. Components of the basal ganglia include the caudate nucleus, putamen, globus pallidus, lentiform nucleus, and substantia nigra. The basal ganglia are primarily involved in the control of motor activities; deficits in this area are significant in movement disorders such as Parkinson disease and Huntington chorea. Certain medications used to treat these movement disorders exert their effects by interacting with basal ganglia structures.

The largest and most rostral aspect of the brain is the cerebrum (see Fig. 51). The cerebrum consists of bilateral hemispheres, with each hemisphere anatomically divided into several lobes (frontal, temporal, parietal,



SECTION 2 Pharmacology of the Central Nervous System

Corpus Skull callosum Cerebrum

Meninges Thalamus

significant in its control over the function of hormonal release from the pituitary gland. Several CNS drugs affecting sensation and control of the body functions listed, manifest their effects by interacting with the thalamus and hypothalamus.

Mesencephalon and Brainstem

The mesencephalon, or midbrain, serves as a bridge between the higher areas of the brain (cerebrum and diencephalon) and the brainstem. The brainstem consists of the pons and the medulla oblongata. In addition to serving as a pathway between the higher brain and spinal cord, the midbrain and brainstem are the locations of centers responsible for controlling respiration and cardiovascular function (vasomotor center). The reticular formation is also located in the midbrain and brainstem. The reticular formation is comprised of a collection of neurons that extend from the reticular substance of the upper spinal cord through the midbrain and the thalamus. The reticular formation monitors and controls consciousness and is also important in regulating the amount of arousal or alertness in the cerebral cortex. Consequently, CNS drugs that affect the arousal state of the individual tend to exert their effects on the reticular formation. Sedative-hypnotics and general anesthetics tend to decrease activity in the reticular formation, whereas certain CNS stimulants (caffeine, amphetamines) may increase arousal through a stimulatory effect on reticular formation neurons.

Pons Medulla




Spinal cord



The cerebellum lies posterior to the brainstem and is separated from it by the fourth ventricle. Anatomically it is divided into two hemispheres, each consisting of three lobes (anterior, posterior, and flocculonodular). The function of the cerebellum is to help plan and coordinate motor activity and to assume responsibility for comparing the actual movement with the intended motor pattern. The cerebellum interprets various sensory input and helps modulate motor output so that the actual movement closely resembles the intended motor program. The cerebellum is also concerned with the vestibular mechanisms responsible for maintaining balance and posture. Therapeutic medications are not usually targeted directly for the cerebellum, but incoordination and other movement disorders may result if a drug exerts a toxic side effect on the cerebellum.

FIGURE 51 General organization of the CNS.

The area of the brain enclosing the third ventricle is the diencephalon. This area consists of several important structures, including the thalamus and hypothalamus. The thalamus contains distinct nuclei that are crucial in the integration of certain types of sensations and their relay to other areas of the brain (such as the somatosensory cortex). The hypothalamus is involved in the control of diverse body functions including temperature control, appetite, water balance, and certain emotional reactions. The hypothalamus is also

Chapter 5 General Principles of Central Nervous System Pharmacology


Limbic System
So far, all of the structures described have been grouped primarily by their anatomic relationships with the brain. The limbic system is comprised of several structures that are dispersed throughout the brain but are often considered as a functional unit or system within the CNS. Major components of the limbic system include cortical structures (such as the amygdala, hippocampus, and cingulate gyrus), the hypothalamus, certain thalamic nuclei, mamillary bodies, septum pellucidum, and several other structures and tracts. These structures are involved in the control of emotional and behavioral activity. Certain aspects of motivation, aggression, sexual activity, and instinctive responses may be influenced by activity within the limbic system. CNS drugs affecting these aspects of behavior, including some antianxiety and antipsychotic medications, are believed to exert their beneficial effects primarily by altering activity in the limbic structures.

Spinal Cord
At the caudal end of the brainstem, the CNS continues distally as the spinal cord. The spinal cord is cylindrically shaped and consists of centrally located gray matter that is surrounded by white matter. The gray matter serves as an area for synaptic connections between various neurons. The white matter consists of the myelinated axons of neurons, which are grouped into tracts ascending or descending between the brain and specific levels of the cord. Certain CNS drugs exert some or all of their effects by modifying synaptic transmission in specific areas of gray matter, while other CNS drugs, such as narcotic analgesics, may exert an effect on synaptic transmission in the gray matter of the cord as well as on synapses in other areas of the brain. Some drugs may be specifically directed toward the white matter of the cord. Drugs such as local anesthetics can be used to block action potential propagation in the white matter so that ascending or descending information is interrupted (i.e., a spinal block).

The Blood-Brain Barrier

The blood-brain barrier refers to the unique structure and function of CNS capillaries.15,43 Certain substances are not able to pass from the bloodstream into the CNS, despite the fact that these substances are able to pass from the systemic circulation into other

peripheral tissues. This fact suggests the existence of some sort of unique structure and function of the CNS capillaries that prevents many substances from entering the brain and spinal cordhence, the term blood-brain barrier. This barrier effect is caused primarily by the tight junctions that occur between capillary endothelial cells; in fact, CNS capillaries lack the gaps and fenestrations that are seen in peripheral capillaries. Also, nonneuronal cells in the CNS (e.g., astrocytes) and the capillary basement membrane seem to contribute to the relative impermeability of this barrier. Functionally, the blood-brain barrier acts as a selective filter and seems to protect the CNS by limiting the harmful substances that enter into the brain and spinal cord. The blood-brain barrier obviously plays an important role in clinical pharmacotherapeutics. To exert their effects, drugs targeted for the CNS must be able to pass from the bloodstream into the brain and spinal cord. In general, nonpolar, lipid-soluble drugs are able to cross the blood-brain barrier by passive diffusion.6,13 Polar and lipophobic compounds are usually unable to enter the brain. Some exceptions occur because of the presence of carrier-mediated transport systems in the blood-brain barrier.23 Some substances (such as glucose) are transported via facilitated diffusion, while other compounds (including some drugs) may be able to enter the brain by active transport. However, the transport processes that carry drugs into the brain are limited to certain specific compounds, and the typical manner by which most drugs enter the brain is by passive lipid diffusion.20 Several active transport systems also exist on the blood-brain barrier that are responsible for removing drugs and toxins from the brain.6,11 That is, certain drugs can enter the brain easily via diffusion or another process, but these drugs are then rapidly and efficiently transported out of the brain and back into the systemic circulation.6,13 This effect creates an obvious problem because these drugs will not reach therapeutic levels within the CNS, and wont be beneficial. Hence, the blood-brain barrier has many structural and functional characteristics that influence CNS drugs, and researchers continue to explore ways that these characteristics can be modified to ensure adequate drug delivery to the brain and spinal cord.15,23

CNS Neurotransmitters
The majority of neural connections in the human brain and spinal cord are characterized as chemical


SECTION 2 Pharmacology of the Central Nervous System

Table 51
Transmitter Acetylcholine

Primary CNS Location Cerebral cortex (many areas); basal ganglia; limbic and thalamic regions; spinal interneurons Neurons originating in brainstem and hypothalamus that project throughout other areas of brain Basal ganglia; limbic system Neurons originating in brainstem that project upward (to hypothalamus) and downward (to spinal cord) Interneurons throughout the spinal cord, cerebellum, basal ganglia, cerebral cortex Interneurons in spinal cord and brainstem Interneurons throughout brain and spinal cord Pathways in spinal cord and brain that mediate painful stimuli Pain suppression pathways in spinal cord and brain General Effect Excitation



Dopamine Serotonin

Inhibition Inhibition

GABA (gamma-aminobutyric acid)


Glycine Glutamate, aspartate Substance P

Inhibition Excitation Excitation



synapses. The term chemical synapse indicates that a chemical neurotransmitter is used to propagate the nervous impulse across the gap that exists between two neurons. Several distinct chemicals have been identified as neurotransmitters within the brain and spinal cord (Table 51). Groups of neurons within the CNS tend to use one of these neurotransmitters to produce either excitation or inhibition of the other neurons. Although each neurotransmitter can be generally described as either excitatory or inhibitory within the CNS, some transmitters may have different effects depending on the nature of the postsynaptic receptor involved. As discussed in Chapter 4, the interaction of the transmitter and the receptor dictates the effect on the postsynaptic neuron. The fact that several distinct neurotransmitters exist and that neurons using specific transmitters are organized functionally within the CNS has important pharmacologic implications. Certain drugs may alter the transmission in pathways using a specific neurotransmitter while having little or no effect on other transmitter pathways. This allows the drug to exert a

rather specific effect on the CNS, so many disorders may be rectified without radically altering other CNS functions. Other drugs may have a much more general effect and may alter transmission in many CNS regions. To provide an indication of neurotransmitter function, the major categories of CNS neurotransmitters and their general locations and effects are discussed subsequently.

Acetylcholine is the neurotransmitter found in many areas of the brain as well as in the periphery (skeletal neuromuscular junction, some autonomic synapses). In the brain, acetylcholine is abundant in the cerebral cortex, and seems to play a critical role in cognition and memory.22,32 Neurons originating in the large pyramidal cells of the motor cortex and many neurons originating in the basal ganglia also secrete acetylcholine from their terminal axons. In general, acetylcholine synapses in the CNS are excitatory in nature.

Chapter 5 General Principles of Central Nervous System Pharmacology


Monoamines are a group of structurally similar CNS neurotransmitters that include the catecholamines (dopamine, norepinephrine) and 5-hydroxytryptamine (serotonin).36 Dopamine exerts different effects at various locations within the brain.29,37 Within the basal ganglia, dopamine is secreted by neurons that originate in the substantia nigra and project to the corpus striatum. As such, it is important in regulating motor control, and the loss of these dopaminergic neurons results in symptoms commonly associated with Parkinson disease (see Chapter 10). Dopamine also influences mood and emotions, primarily via its presence in the hypothalamus and other structures within the limbic system. Although its effects within the brain are very complex, dopamine generally inhibits the neurons onto which it is released. Norepinephrine is secreted by neurons that originate in the locus caeruleus of the pons and projects throughout the reticular formation. Norepinephrine is generally regarded as an inhibitory transmitter within the CNS, but the overall effect following activity of norepinephrine synapses is often general excitation of the brain, probably because norepinephrine directly inhibits other neurons that produce inhibition. This phenomenon of disinhibition causes excitation by removing the influence of inhibitory neurons. Serotonin (also known as 5-hydroxytryptamine) is released by cells originating in the midline of the pons and brainstem and is projected to many different areas, including the dorsal horns of the spinal cord and the hypothalamus. Serotonin is considered to be a strong inhibitor in most areas of the CNS and is believed to be important in mediating the inhibition of painful stimuli. It is also involved in controlling many aspects of mood and behavior, and problems with serotonergic activity have been implicated in several psychiatric disorders, including depression and anxiety.12,17 The roles of serotonin and the other monoamines in psychiatric disorders are discussed in Chapters 68.

of the brain.4,8 Likewise, GABA is found throughout the CNS, and is believed to be the primary neurotransmitter used to cause inhibition at presynaptic and postsynaptic neurons in the brain and spinal cord.5,10,26,30 Other amino acids such as aspartate and glutamate have been found in high concentrations throughout the brain and spinal cord; these substances cause excitation of CNS neurons.2,3,42 These excitatory amino acids have received a great deal of attention lately because they may also produce neurotoxic effects when released in large amounts during CNS injury and certain neurologic disorders (epilepsy, amyotrophic lateral sclerosis, and so forth).1,2,3,16

Many peptides have already been established as CNS neurotransmitters.25 One peptide that is important from a pharmacologic standpoint is substance P, which is an excitatory transmitter that is involved in spinal cord pathways transmitting pain impulses.14,19,38 Increased activity at substance P synapses in the cord serves to mediate the transmission of painful sensations, and certain drugs such as the opioid analgesics may decrease activity at these synapses. Other peptides that have important pharmacologic implications include three families of compounds: the endorphins, enkephalins, and dynorphins.21 These peptides, also known as the endogenous opioids, are excitatory transmitters in certain brain synapses that inhibit painful sensations. Hence, endogenous opioids in the brain are able to decrease the central perception of pain. The interaction of these compounds with exogenous opioid drugs is discussed in Chapter 14. Finally, peptides such as galanin, leptin, neuropeptide Y, vasoactive intestinal polypeptide (VIP), and pituitary adenylate cyclaseactivating polypeptide (PACAP) have been identified in various areas of the CNS. These and other peptides may affect various CNS functions, either by acting directly as neurotransmitters or by acting as cotransmitters moderating the effects of other neurotransmitters.7,24,27,34

Amino Acids
Several amino acids, such as glycine and gammaaminobutyric acid (GABA), are important inhibitory transmitters in the brain and spinal cord. Glycine seems to be the inhibitory transmitter used by certain interneurons located throughout the spinal cord, and this amino acid also causes inhibition in certain areas

Other Transmitters
In addition to the well-known substances, other chemicals are continually being identified as potential CNS neurotransmitters. Recent evidence has implicated substances such as adenosine and adenosine triphosphate (ATP) as transmitters or modulators of neural transmission in specific areas of the brain and in the


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autonomic nervous system.31,39 Many other chemicals that are traditionally associated with functions outside the CNS are being identified as possible CNS transmitters, including histamine, nitric oxide, and certain hormones (vasopressin, oxytocin).9,33 As the function of these chemicals and other new transmitters becomes clearer, the pharmacologic significance of drugs that affect these synapses will undoubtedly be considered.

the stimulation of postsynaptic receptors, or both. When considering a typical synapse, such as the one shown in Figure 52, there are several distinct sites at which a drug may alter activity in the synapse. Specific ways a drug may modify synaptic transmission are presented here. 1. Presynaptic action potential. The arrival of an action potential at the presynaptic terminal initiates neurotransmitter release. Certain drugs, such as local anesthetics, block propagation along neural axons so that the action potential fails to reach the presynaptic terminal, which effectively eliminates activity at that particular synapse. Also, the amount of depolarization or the height of the action potential arriving at the presynaptic terminal is directly related to the amount of transmitter released. Any drug or endogenous chemical that limits the amount of depolarization occurring in the presynaptic terminal will inhibit the synapse because less neurotransmitter is released. In certain situations, this is referred to as presynaptic inhibition, because the site of this effect is at the presynaptic terminal. The endogenous neurotransmitter GABA is believed to exert some of its inhibitory effects via this mechanism. 2. Synthesis of neurotransmitter. Drugs that block the synthesis of neurotransmitter will eventually deplete the presynaptic terminal and impair transmission. For example, metyrosine (Demser)

CNS Drugs: General Mechanisms

The majority of CNS drugs work by modifying synaptic transmission in some way. Figure 52 shows a typical chemical synapse that is found in the CNS. Most drugs that attempt to rectify CNS-related disorders do so by either increasing or decreasing transmission at specific synapses. For instance, psychotic behavior has been associated with overactivity in central synapses that use dopamine as a neurotransmitter (see Chapter 8). Drug therapy in this situation consists of agents that decrease activity at central dopamine synapses. Conversely, Parkinson disease results from a decrease in activity at specific dopamine synapses (see Chapter 10). Antiparkinsonian drugs attempt to increase dopaminergic transmission at these synapses and bring synaptic activity back to normal levels. A drug that modifies synaptic transmission must somehow alter the quantity of the neurotransmitter that is released from the presynaptic terminal or affect

1. Action Potential 3. Storage

4. Release

5. Reuptake 2. Synthesis

7. Post-synaptic receptor

6. Degradation

8. Pre-synaptic "Autoreceptor"

9. Membrane

FIGURE 52 Sites at which drugs can alter transmission at a CNS synapse.

Chapter 5 General Principles of Central Nervous System Pharmacology






inhibits an enzyme that is essential for catecholamine biosynthesis in the presynaptic terminal. Treatment with metyrosine results in decreased synthesis of transmitters such as dopamine and norepinephrine. Storage of neurotransmitter. A certain amount of chemical transmitter is stored in presynaptic vesicles. Drugs that impair this storage will decrease the ability of the synapse to continue to transmit information for extended periods. An example of this is the antihypertensive drug reserpine (Serpalan, Serpasil), which impairs the ability of adrenergic terminals to sequester and store norepinephrine in presynaptic vesicles. Release. Certain drugs will increase synaptic activity by directly increasing the release of neurotransmitter from the presynaptic terminal. Amphetamines appear to exert their effects on the CNS primarily by increasing the presynaptic release of catecholamine neurotransmitters (e.g., norepinephrine). Conversely, other compounds may inhibit the synapse by directly decreasing the amount of transmitter released during each action potential. An example is botulinum toxin (Botox), which can be used as a skeletal muscle relaxant because of its ability to impair the release of acetylcholine from the skeletal neuromuscular junction (see Chapter 13). Reuptake. After the neurotransmitter is released, some chemical synapses terminate activity primarily by transmitter reuptake. Reuptake involves the movement of the transmitter molecule back into the presynaptic terminal. A drug that impairs the reuptake of transmitter allows more of it to remain in the synaptic cleft and continue to exert an effect. Consequently, blocking reuptake actually increases activity at the synapse. For instance, tricyclic antidepressants (see Chapter 7) impair the reuptake mechanism that pumps amine neurotransmitters back into the presynaptic terminal, which allows the transmitter to continue to exert its effect and prolong activity at the synapse. Degradation. Some synapses rely primarily on the enzymatic breakdown of the released transmitter to terminate synaptic activity. Inhibition of the enzyme responsible for terminating the transmitter allows more of the active transmitter to remain in the synaptic cleft, thereby increasing activity at the synapse. An example is using a drug that inhibits the cholinesterase

enzyme as a method of treating myasthenia gravis. In myasthenia gravis, there is a functional decrease in activity at the skeletal neuromuscular junction. Anticholinesterase drugs such as neostigmine (Prostigmin) and pyridostigmine (Mestinon) inhibit acetylcholine breakdown, allowing more of the released neurotransmitter to continue to exert an effect at the neuromuscular synapse. 7. Postsynaptic receptor. As discussed in Chapter 4, chemical antagonists can be used to block the postsynaptic receptor, thus decreasing synaptic transmission. The best-known example of this is the use of beta blockers. These agents are antagonists that are specific for the beta-adrenergic receptors on the myocardium, and they are frequently used to treat hypertension, cardiac arrhythmias, and angina pectoris. Other drugs may improve synaptic transmission by affecting the receptor directly so there is a tendency for increased neurotransmitter binding or improved receptoreffector coupling, or both. For instance, benzodiazepines (e.g., diazepam [Valium], chlordiazepoxide [Librium, others]) appear to enhance the postsynaptic effects of the inhibitory neurotransmitter GABA. 8. Presynaptic autoreceptors. In addition to postsynaptic receptors, there are also receptors on the presynaptic terminal of some types of chemical synapses. These presynaptic receptors seem to serve as a method of negative feedback in controlling neurotransmitter release. 18,35 During high levels of synaptic activity, the accumulation of neurotransmitter in the synaptic cleft may allow binding to the presynaptic receptors and limit further release of chemical transmitter. Certain drugs may also be able to attenuate synaptic activity through presynaptic autoreceptors. For instance, clonidine (Catapres), may exert some of its antihypertensive effects by binding to presynaptic receptors on sympathetic postganglionic neurons and impairing the release of norepinephrine onto the peripheral vasculature. The use of drugs that alter synaptic activity by binding to these autoreceptors is still somewhat new, however, and the full potential for this area of pharmacology remains to be determined. 9. Membrane effects. Drugs may alter synaptic transmission by affecting membrane organization and fluidity. Membrane fluidity is basically


SECTION 2 Pharmacology of the Central Nervous System

the amount of flexibility or mobility of the lipid bilayer. Drugs that alter the fluidity of the presynaptic membrane could affect the way that presynaptic vesicles fuse with and release their neurotransmitter. Drug-induced changes in the postsynaptic membrane would affect the receptor environment and thereby alter receptor function. Membrane modification will result in either increased or decreased synaptic transmission, depending on the drug in question and the type and magnitude of membrane change. Alcohol (ethanol) and general anesthetics were originally thought to exert their effects by producing reversible changes in the fluidity and organization of the cell membranes of central neurons. Although this idea has been challenged somewhat, these drugs may still exert some of their effects via neuronal membranes. A CNS drug does not have to adhere specifically to only one of these methods of synaptic modifica-

tion. Some drugs may affect the synapse in two or more ways. For example, the antihypertensive agent guanethidine (Ismelin) impairs both presynaptic storage and release of norepinephrine. Other drugs such as barbiturates may affect both the presynaptic terminal and the postsynaptic receptor in CNS synapses.

Drugs affecting the brain and spinal cord usually exert their effects by somehow modifying synaptic transmission. In some instances, drugs may be targeted for specific synapses in an attempt to rectify some problem with transmission at that particular synapse. Other drugs may increase or decrease the excitability of CNS neurons in an attempt to have a more general effect on the overall level of consciousness of the individual. Specific categories of CNS drugs and their pharmacodynamic mechanisms are discussed in succeeding chapters.

1. Aarts MM, Tymianski M. Novel treatment of excitotoxicity: targeted disruption of intracellular signaling from glutamate receptors. Biochem Pharmacol. 2003;66:877886. 2. Arundine M, Tymianski M. Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium. 2003;34:325337. 3. Arundine M, Tymianski M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci. 2004; 61:657668. 4. Awatramani GB, Turecek R, Trussell LO. Inhibitory control at a synaptic relay. J Neurosci. 2004;24: 26432647. 5. Barral J, Toro S, Galarraga E, Bargas J. GABAergic presynaptic inhibition of rat neostriatal afferents is mediated by Q-type Ca(2 ) channels. Neurosci Lett. 2000;283:3336. 6. Begley DJ. ABC transporters and the blood-brain barrier. Curr Pharm Des. 2004;10:12951312. 7. Bjorbaek C, Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res. 2004;59:305331. 8. Breustedt J, Schmitz D, Heinemann U, Schmieden V. Characterization of the inhibitory glycine receptor on entorhinal cortex neurons. Eur J Neurosci. 2004; 19:19871991. 9. Cherian L, Hlatky R, Robertson CS. Nitric oxide in traumatic brain injury. Brain Pathol. 2004;14:195201. 10. Ciranna L, Licata F, Li Volsi G, Santangelo F. Role of GABA A and GABA B receptors in GABA-induced 11. 12. 13.


15. 16. 17.

18. 19.

inhibition of rat red nucleus neurons. Neurosci Lett. 2003;341:221224. de Boer AG, van der Sandt IC, Gaillard PJ. The role of drug transporters at the blood-brain barrier. Annu Rev Pharmacol Toxicol. 2003;43:629656. Elhwuegi AS. Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:435451. Elsinga PH, Hendrikse NH, Bart J, Vaalburg W, van Waarde A. PET Studies on P-glycoprotein function in the blood-brain barrier: how it affects uptake and binding of drugs within the CNS. Curr Pharm Des. 2004;10:14931503. Fras C, Kravetz P, Mody DR, Heggeness MH. Substance P-containing nerves within the human vertebral body. An immunohistochemical study of the basivertebral nerve. Spine J. 2003;3:6367. Fricker G, Miller DS. Modulation of drug transporters at the blood-brain barrier. Pharmacology. 2004;70: 169176. Gillessen T, Budd SL, Lipton SA. Excitatory amino acid neurotoxicity. Adv Exp Med Biol. 2002;513: 340. Gingrich JA, Ansorge MS, Merker R, Weisstaub N, Zhou M. New lessons from knockout mice: the role of serotonin during development and its possible contribution to the origins of neuropsychiatric disorders. CNS Spectr. 2003;8:572577. Gothert M. Modulation of noradrenaline release in human cardiovascular tissues. Pharmacol Toxicol. 2003;92:156159. Guo TZ, Offley SC, Boyd EA, Jacobs CR, Kingery WS. Substance P signaling contributes to the vascular

Chapter 5 General Principles of Central Nervous System Pharmacology and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I. Pain. 2004;108:95107. Habgood MD, Begley DJ, Abbott NJ. Determinants of passive drug entry into the central nervous system. Cell Mol Neurobiol. 2000;20:231253. Janecka A, Fichna J, Janecki T. Opioid receptors and their ligands. Curr Top Med Chem. 2004;4:117. Jones BE. Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex. Prog Brain Res. 2004;145:157169. Kabanov AV, Batrakova EV. New technologies for drug delivery across the blood brain barrier. Curr Pharm Des. 2004;10:13551363. Kalra SP, Kalra PS. Neuropeptide Y. A physiological orexigen modulated by the feedback action of ghrelin and leptin. Endocrine. 2003;22:4956. Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 2000. Ma CL, Kelly JB, Wu SH. Presynaptic modulation of GABAergic inhibition by GABA(B) receptors in the rats inferior colliculus. Neuroscience. 2002;114: 207215. Morilak DA, Cecchi M, Khoshbouei H. Interactions of norepinephrine and galanin in the central amygdala and lateral bed nucleus of the stria terminalis modulate the behavioral response to acute stress. Life Sci. 2003;73:715726. Nicholls JG, Martin AR, Wallace BG, Fuchs PA. From Neuron to Brain. 4th ed. Sunderland, MA: Sinauer Associates; 2001. Nieoullon A, Coquerel A. Dopamine: a key regulator to adapt action, emotion, motivation and cognition. Curr Opin Neurol. 2003;(suppl 2):S3S9. Parnas I, Rashkovan G, Ravin R, Fischer Y. Novel mechanism for presynaptic inhibition: GABA(A) receptors affect the release machinery. J Neurophysiol. 2000;84:12401246.


20. 21. 22. 23. 24. 25. 26.


28. 29. 30.

31. Pearson T, Currie AJ, Etherington LA, et al. Plasticity of purine release during cerebral ischemia: clinical implications? J Cell Mol Med. 2003;7:362375. 32. Pepeu G, Giovannini MG. Changes in acetylcholine extracellular levels during cognitive processes. Learn Mem. 2004;11:2127. 33. Philippu A, Prast H. Importance of histamine in modulatory processes, locomotion and memory. Behav Brain Res. 2001;124:151159. 34. Pozo D. VIP- and PACAP-mediated immunomodulation as prospective therapeutic tools. Trends Mol Med. 2003;9:211217. 35. Raiteri M. Presynaptic autoreceptors. J Neurochem. 2001;78:673675. 36. Schweighofer N, Doya K, Kuroda S. Cerebellar aminergic neuromodulation: towards a functional understanding. Brain Res Brain Res Rev. 2004; 44:103116. 37. Smidt MP, Smits SM, Burbach JP. Molecular mechanisms underlying midbrain dopamine neuro development and function. Eur J Pharmacol. 2003; 480:7588. 38. Vachon P, Masse R, Gibbs BF. Substance P and neurotensin are up regulated in the lumbar spinal cord of animals with neuropathic pain. Can J Vet Res. 2004; 68:8692. 39. Volonte C, Amadio S, Cavaliere F, DAmbrosi N, Vacca F, Bernardi G. Extracellular ATP and neurodegeneration. Curr Drug Targets CNS Neurol Disord. 2003;2:403412. 40. Waxman SG. Clinical Neuroanatomy. 25th ed. New York: McGraw-Hill; 2003. 41. Webster RA , ed. Neurotransmitters, Drugs, and Brain Function. New York: John Wiley and Sons; 2001. 42. Willis C, Lybrand S, Bellamy N. Excitatory amino acid inhibitors for traumatic brain injury. Cochrane Database Syst Rev. 2004;CD003986. 43. Wolburg H, Lippoldt A. Tight junctions of the bloodbrain barrier: development, composition and regulation. Vascul Pharmacol. 2002;38:323337.

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Sedative-Hypnotic and Antianxiety Agents

Drugs that are classified as sedative-hypnotics are used both to relax the patient and to promote sleep.59 As the name sedative implies, these drugs exert a calming effect and serve to pacify the patient. At higher doses, the same drug can produce drowsiness and initiate a relatively normal state of sleep (hypnosis). At still higher doses, some sedative-hypnotics (especially barbiturates) will eventually bring on a state of general anesthesia. Because of their general central nervous system (CNS)-depressant effects, some sedativehypnotic drugs are also used for other functions such as treating epilepsy or producing muscle relaxation. However, the sleep-enhancing effects will be of concern in this chapter. By producing sedation, many drugs will also decrease the level of anxiety in a patient. Of course, these anxiolytic properties often cause a decrease in the level of alertness in the individual. However, certain agents are available that can reduce anxiety without an overt sedative effect. Those medications that selectively produce antianxiety effects are discussed later in this chapter. Sedative-hypnotic and antianxiety drugs are among the most commonly used drugs worldwide. For example, it is estimated that insomnia affects between 10 to 15 percent of the general population, and that pharmacological management can be helpful in promoting normal sleep.18,42 Moreover, people who are ill, or who have recently been relocated to a new environment (hospital, nursing home), will often have difficulty sleeping and might need some form of sedative-hypnotic agent.8,35,41 Likewise, a person who sustains an injury or illness will certainly have some apprehension concerning his or her welfare.33 If necessary, this apprehension can be controlled to some extent by using antianxiety drugs during the course of rehabilitation. Consequently, many patients receiving physical therapy and occupational therapy take sedative-hypnotic and antianxiety agents to help promote sleep and decrease anxiety; rehabilitation specialists should understand the basic pharmacology of these agents.

Sedative-Hypnotic Agents
Sedative-hypnotics fall into two general categories: benzodiazepines and nonbenzodiazepines (Table 61). At present, benzodiazepines are typically used to promote normal sedation and sleep, especially in relatively acute or short-term situations. These agents will be addressed first, followed by a description of the nonbenzodiazepine hypnotics.

Benzodiazepines are a family of compounds that share the same basic chemical structure and pharmacological effects. Although the more famous members of this family are associated with treating anxiety (e.g., diazepam [Valium]; see later in this chapter), several benzodiazepines are indicated specifically to promote sleep (Table 61). These agents exert hypnotic effects similar to those of nonbenzodiazepinessuch as the barbituratesbut benzodiazepines are generally regarded as safer because there is less of a chance for lethal overdose.22 Benzodiazepines, however, are not without their drawbacks, and they can cause resid65


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Table 61


Oral Adult Dose (mg) Generic Name Barbiturates Amobarbital Aprobarbital Butabarbital Pentobarbital Phenobarbital Secobarbital Benzodiazepines** Estazolam Flurazepam Quazepam Temazepam Triazolam Others Chloral hydrate Ethchlorvynol Glutethimide Promethazine Zaleplon Zolpidem Noctec Placidyl (generic) Phenergan, others Sonata Ambien 250 TID 5001000 5001000 250500 2550 10 10 ProSom Dalmane Doral Restoril Halcion 12 1530 7.515 7.530 0.1250.25 Amytal Alurate Busodium, Butisol, others Nembutal Solfoton Seconal 25100 BID or TID 40 TID 1530 TID or QID 20 TID or QID 1540 BID or TID 3050 TID or QID 65200 40160 50100 100 100320 100 Trade Name Sedative Hypnotic*

*Hypnotic doses are typically administered as a single dose at bedtime. **Benzodiazepines listed here are indicated specifically as hypnotic agents and are not approved for other uses (antianxiety, anticonvulsant, and so forth). Virtually all benzodiazepines have sedative-hypnotic effects, and other benzodiazepines may be administered to produce sedation or sleep, depending on the dosage and the patient.

ual effects the day after they are administered; prolonged use can also cause tolerance and physical dependence (see Problems and Adverse Effects, later in this chapter).39,60

Mechanism of Benzodiazepine Effects

The benzodiazepines exert their effects by increasing the inhibitory effects at CNS synapses that use the neurotransmitter gamma-aminobutyric acid (GABA).48,49 These inhibitory synapses are associated with a membrane protein complex containing three primary components: (1) a binding site for GABA, (2) a binding site for benzodiazepines, and (3) an ion channel that is specific for chloride ions (Fig. 61).48,55 GABA typically exerts its inhibitory effects by binding to its receptor site on this complex and by

initiating an increase in chloride conductance through the channel. Increased chloride conductance facilitates chloride entry into the neuron and results in hyperpolarization, or a decreased ability to raise the neuron to its firing threshold. By binding to their own respective site on the complex, benzodiazepines potentiate the effects of GABA and increase the inhibition at these synapses. Consequently, the presence of the GABAbenzodiazepinechloride ion channel complex accounts for the specific mechanism of action of this class of sedative-hypnotics. By increasing the inhibitory effects at GABAergic synapses located in the reticular formation, benzodiazepines can decrease the level of arousal in the individual. In other words, the general excitation level in the reticular activating system decreases, and relaxation and sleep are enhanced.

Chapter 6 Sedative-Hypnotic and Antianxiety Agents

(From Kandel, ER. Disorders of mood: depression, mania, and anxiety disorders. In: Kandel ER, Schwartz JH, and Jessell TM, eds. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 2000: 882, with permission.)


Chloride channel Barbiturate Benzo GABA


FIGURE 61 Putative structure of the GABA-benzodiazepine-chloride ion channel complex. The centrally located chloride ion channel is modulated by the binding of GABA to the alpha subunit of the receptor. The binding and effects of GABA are enhanced by the binding of benzodiazepines to the gamma subunits or barbiturates to the beta subunit.

Research has also indicated that there are at least three primary types of GABA receptors, and these receptors are classified as GABA A, B, and C according to their structural and functional characteristics.5,28,49 GABA A and GABAC receptors, for example, cause inhibition by increasing chloride entry, whereas GABAB receptors may cause inhibition by increasing potassium exit (efflux) from CNS neurons.14 At the present time, it appears that benzodiazepines act primarily on the GABAA subtype and that the therapeutic effects of these drugs (sedation, hypnosis, decreased anxiety) are mediated through the GABAA receptor, which is found in the brain.3,48,49 Hence, clinically used benzodiazepines are basically GABAA receptor agonists. Furthermore, the GABAA receptor is composed of several subunits (alpha, beta, gamma); it appears that individual subunits on this receptor mediate specific effects.3,11 Sedation, for example, seems to be mediated by the alpha 1 subunit, whereas other beneficial effects such as decreased anxiety might be mediated by the alpha 2 and alpha 3 subunits. Benzodiazepines seem to affect all of these subunits, hence their ability to produce sedative and antianxiety effects.3 These drugs, however, might also exert certain side effects (tolerance, dependence) by affecting other subunits on the GABAA receptor. A drug that is selective for only the alpha 1 subunit might exert sedative effects without producing as many side effects. Some of the newer nonbenzodiazepine drugs such as zolpi-

dem (Ambien) and zaleplon (Sonata) appear to be more specific for the alpha 1 subunit, and might therefore produce sedative effects with fewer side effects.51 These newer drugs are addressed later in this chapter. Because of these new advances, scientists continue to study the molecular biology of the GABAA receptor, and clarify how benzodiazepines affect these receptors. Likewise, differences between the principal GABA receptors (A, B, C) has encouraged the development of drugs that are more selective to GABA receptors located in certain areas of the CNS. The muscle relaxant baclofen (Lioresal), for example, may be somewhat more selective for GABAB receptors in the spinal cord than for other GABAA or GABAC receptors that are found in the brain (see Chapter 13). Future drug development will continue to exploit the differences between the GABA receptor subtypes so that drugs are more selective and can produce more specific beneficial effects with fewer side effects. Finally, the discovery of a CNS receptor that is specific for benzodiazepines has led to some interesting speculation as to the possible existence of some type of endogenous sedative-like agent. The presence of a certain type of receptor to indicate that the body produces an appropriate agonist for that receptor makes sense. For instance, the discovery of opiate receptors initiated the search for endogenous opiate-like substances, which culminated in the discovery of the enkephalins. It has been surmised that certain endogenous steroids such as allopregnanolone (a metabolic byproduct of


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progesterone) can bind to the GABA receptors in the CNS and produce sedative-hypnotic effects. Continued research in this area may someday reveal the exact role of steroids and other endogenous substances, and the focus of pharmacologic treatment can then be directed toward stimulating the release of endogenous sedative-hypnotic agents

by this more extensive CNS depression is discussed in Chapter 11.

Newer, Nonbenzodiazepine Sedative-Hypnotics

Several drugs including zolpidem (Ambien) and zaleplon (Sonata) were developed recently as sedativehypnotics.19,25 These drugs are chemically different from the benzodiazepines, but still seem to affect the GABAA receptors in the brain. That is, these newer drugs bind to the GABAA receptor, which then causes GABA to bind more effectively, thus increasing chloride conductance and the level of inhibition in the neuron. Increased inhibition in certain areas of the brain results in less arousal and the promotion of sleep. These newer drugs appear to be as effective as the benzodiazepines in promoting sleep. The drugs also seem to have a lower risk of producing certain side effects and causing problems when discontinued (see Problems and Adverse Effects, below).20,25,62 This difference might be explained by the fact that newer, nonbenzodiazepine drugs bind preferentially to the alpha 1 subunit of the GABAA receptor.19,51,52 As discussed earlier, stimulation of this particular subunit seems to mediate sedation without producing other side effects. Hence, drugs like zolpidem and zaleplon are gaining acceptance for the treatment of sleep disorders, and efforts continue to develop other nonbenzodiazepine drugs that selectively affect this receptor.

The barbiturates are a group of CNS depressants that share a common chemical origin: barbituric acid. The potent sedative-hypnotic properties of these drugs have been recognized for some time, and their status as the premier medication used to promote sleep went unchallenged for many years. However, barbiturates are associated with a relatively small therapeutic index; approximately 10 times the therapeutic dose can often be fatal. These drugs are also very addictive, and their prolonged use is often a problem in terms of drug abuse. Consequently, the lack of safety of the barbiturates and their strong potential for addiction and abuse necessitated the development of alternative nonbarbiturate drugs such as the benzodiazepines. Still, some barbiturates are occasionally used for their hypnotic properties; these drugs are listed in Table 61. Despite their extensive use in the past, the exact mechanism of the barbiturates remains somewhat unclear. When used in sedative-hypnotic doses, barbiturates may function in a similar fashion to the benzodiazepines in that they also potentiate the inhibitory effects of GABA.21 This idea suggests that barbiturates may affect the GABA-benzodiazepinechloride ion channel complex described above.21 Indeed, considerable evidence exists that barbiturates bind directly to the GABAA receptor at a site that is different from the binding site for GABA or benzodiazepines (see Fig. 61).21 Barbiturates may, however, also exert effects that are not mediated through an effect on the GABAbenzodiazepinechloride ion channel. At higher doses, for instance, barbiturates may also directly increase the release of inhibitory transmitters such as glycine, and increase the release of excitatory transmitters such as glutamate.21,30 Regardless of their exact mechanism, barbiturates are effective sedative-hypnotics because of their specificity for neurons in the midbrain portion of the reticular formation as well as some limbic system structures. At higher doses, barbiturates also depress neuronal excitability in other areas of the brain and spinal cord. Their role in producing general anesthesia

Other Nonbenzodiazepines
Several other nonbenzodiazepine compounds can be prescribed for their sedative-hypnotic properties (see Table 61). These compounds are chemically dissimilar from one another, but share the ability to promote relaxation and sleep via depressing the CNS. Cyclic ethers and alcohols (including ethanol) can be included in this category, but their use specifically as sedativehypnotics is fairly limited at present. The recreational use of ethanol in alcoholic beverages is an important topic in terms of abuse and long-term effects. However, since this area is much too extensive to be addressed here, only their effects as sedative-hypnotics is considered. Alcohol (ethanol) and other sedative-hypnotics neither benzodiazepine nor barbiturate in nature work through mechanisms that are poorly understood. In the past, it was thought that alcohols exerted their CNS-depressant effects directly on neuronal membrane composition and fluidity. These and other high-

Chapter 6 Sedative-Hypnotic and Antianxiety Agents


ly lipid-soluble substances could simply dissolve in the lipid bilayer and inhibit neuronal excitability by temporarily disrupting membrane structures in the presynaptic and postsynaptic regions of CNS neurons.17 Recent evidence, however, suggests that alcohol may act on protein receptors much in the same way as the benzodiazepines and barbiturates. That is, alcohol may exert most of its effects by activating GABAA receptors and increasing GABA-mediated inhibition in the CNS.17,31 In any event, alcohol and similar agents bring about a decrease in neuronal transmission, which causes fairly widespread CNS depression which accounts for the subsequent sedative effects of such compounds.

Benzodiazepine and nonbenzodiazepine sedativehypnotics are usually highly lipid soluble. They are typically administered orally and are absorbed easily and completely from the gastrointestinal tract. Distribution is fairly uniform throughout the body, and these drugs reach the CNS readily because of their high degree of lipid solubility. Sedative-hypnotics are metabolized primarily by the oxidative enzymes of the drug-metabolizing system in liver cells. Termination of their activity is accomplished either by hepatic enzymes or by storage of these drugs in non-CNS tissues; that is, by sequestering the drugs in adipose and other peripheral tissues, their CNS-depressant effects are not exhibited. However, when the drugs slowly leak out of their peripheral storage sites, they can be redistributed to the brain and can cause low levels of sedation. This occurrence may help explain the hangoverlike feelings that are frequently reported the day after taking sedative-hypnotic drugs. Finally, excretion of these drugs takes place through the kidney after their metabolism in the liver. As with most drug biotransformations, metabolism of sedativehypnotics is essential in creating a polar metabolite that is readily excreted by the kidney.

drowsiness and decreased motor performance the next day.39,60,62 These hangoverlike effects may be caused by the drug being redistributed to the CNS from peripheral storage sites or may simply occur because the drug has not been fully metabolized. Anterograde amnesia is another problem sometimes associated with sedative-hypnotic use.39 The patient may have trouble recalling details of events that occurred for a certain period of time before the drug was taken. Although usually a minor problem, this can become serious if the drug-induced amnesia exacerbates an already existing memory problem, as might occur in some elderly patients. These residual problems can be resolved somewhat by taking a smaller dose or by using a drug with a shorter half-life (see Table 62).60,63 Also, newer nonbenzodiazepine agents such as zolpidem and zaleplon appear to have milder effects, perhaps because of their relatively short half-life and the limited duration of action.32,58 These newer drugs have therefore been advocated in people who are prone to residual effects (e.g., older adults), and people who need to use these drugs for an extended period of time.

Tolerance and Physical Dependence

Another potential problem with long-term sedativehypnotic drug use is that prolonged administration may cause tolerance and physical dependence. Drug tolerance is the need to take more of a drug to exert the same effect. Dependence is described as the onset of withdrawal symptoms if drug administration is ceased. Although these problems were originally thought to be limited to barbiturates, benzodiazepines and other sedative-hypnotics are now recognized as also causing tolerance and dependence when taken continually for several weeks.36 The manner and severity of withdrawal symptoms varies according to the type of drug and the extent of physical dependence.50 Withdrawal after short-term benzodiazepine use may be associated with problems such as sleep disturbances (i.e., so-called rebound insomnia).34,62 As discussed earlier, withdrawal effects seem to be milder with the newer nonbenzodiazepine agents (zolpidem and zaleplon).34,62 Newer agents, however, are not devoid of these problems and care should be taken with prolonged use, especially in people with psychiatric disorders or a history of substance abuse.26 Consequently, the long-term use of these drugs should be avoided, and other nonpharmacologic meth-

Problems and Adverse Effects

Residual Effects
The primary problem associated with sedativehypnotic use is the residual effects that can occur the day after administration. Individuals who take a sedative-hypnotic to sleep at night sometimes complain of


SECTION 2 Pharmacology of the Central Nervous System

Table 62


Time to Peak Plasma Concentration (hr)* 2.0 0.51.0 Relative Half-Life Intermediate Long Comments Rapid oral absorption Long elimination half-life because of active metabolites Daytime drowsiness more likely than with other benzodiazepines Slow oral absorption Rapid oral absorption

Estazolam (ProSom) Flurazepam (Dalmane)

Quazepam (Doral)



Temazepam (Restoril) Triazolam (Halcion)

*Adult oral hypnotic dose.

12 Within 2

Shortintermediate Short

ods of reducing stress and promoting relaxation (e.g., mental imagery, biofeedback) should be instituted before tolerance and physical dependence.40,56 If the sedative-hypnotic drug has been used for an extended period, tapering off the dosage rather than abruptly stopping it has been recommended as a safer way to terminate administration.25

Other Side Effects

Other side effects such as gastrointestinal discomfort (nausea and vomiting), dry mouth, sore throat, and muscular incoordination have been reported, but these occur fairly infrequently and vary according to the exact drug used. Cardiovascular and respiratory depression may also occur, but these problems are dose-related and are usually not significant, except in cases of overdose.

associated with many of these syndromes until the situation is resolved or until the individual is counseled effectively in other methods of dealing with his or her anxiety. Many drugsincluding sedative-hypnoticshave the ability to decrease anxiety levels, but this is usually at the expense of an increase in sedation. Frequently, alleviating anxiety without producing excessive sedation is desirable so that the individual can function at home, on the job, and so on. Consequently, certain drugs are available that have significant anxiolytic properties at doses that produce minimal sedation. Benzodiazepine drugs and other nonbenzodiazepine strategies for dealing with anxiety are discussed here.

As discussed previously, because of their relative safety, the benzodiazepines are typically the front-line drugs used to treat many forms of anxiety.13,16 In terms of anxiolytic properties, diazepam (Valium) is the prototypical antianxiety benzodiazepine (Fig. 62). The extensive use of this drug in treating nervousness and apprehension has made the trade name of this compound virtually synonymous with a decrease in tension and anxiety. When prescribed in anxiolytic dosages, diazepam and certain other benzodiazepines (Table 63) will decrease anxiety without major sedative effects. Some sedation, however, may occur even at anxiolytic dosages; these drugs can be used as sedativehypnotics simply by increasing the dosage.

Antianxiety Drugs
Anxiety can be described as a fear or apprehension over a situation or event that an individual feels is threatening. These events can range from a change in employment or family life to somewhat irrational phobias concerning everyday occurrences. Anxiety disorders can also be classified in several clinical categories including generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, and posttraumatic stress syndrome.54 Antianxiety drugs can help decrease the tension and nervousness

Chapter 6 Sedative-Hypnotic and Antianxiety Agents



Buspirone (BuSpar) is an antianxiety agent that was approved in 1986 for treating general anxiety disorder.2 This agent is not a benzodiazepine. It belongs instead to a drug class known as the azapirones.2 Therefore, buspirone does not act on the GABA receptor, but exerts its antianxiety effects by increasing the effects of 5-hydroxytryptamine (serotonin) in certain areas of the brain.12 Buspirone is basically a serotonin agonist that stimulates certain serotonin receptors, especially the 5-HT1A serotonin receptor subtype.6,10 This increase in serotonergic influence is beneficial in treating general anxiety disorder and possibly in panic disorder, obsessive-compulsive disorder, posttraumatic stress syndrome, and various other disorders that are influenced by CNS serotonin levels.7 More importantly, buspirone has a much better side-effect profile than traditional antianxiety drugs. Buspirone seems to produce less sedation and psychomotor impairment than benzodiazepine agents.2 There is a much smaller risk of developing tolerance and dependence to buspirone and the potential for abuse is much lower than with other anxiolytics.57 Buspirone has only moderate efficacy, however, and this drug may not take effect as quickly in patients with severe anxiety.57 Nonetheless, buspirone offers a

FIGURE 62 Diazepam (Valium).

The mechanism of action of the benzodiazepines was discussed previously in this chapter. The antianxiety properties of these drugs involve a mechanism similar or identical to their sedative-hypnotic effects (i.e., potentiating GABAergic transmission).37 Benzodiazepines also seem to increase inhibition in the spinal cord, which produces some degree of skeletal muscle relaxation, which may contribute to their antianxiety effects by making the individual feel more relaxed. The use of these drugs as skeletal muscle relaxants is further discussed in Chapter 13.

Table 63
Generic Name Alprazolam Chlordiazepoxide Clonazepam Clorazepate Diazepam Halazepam Lorazepam Oxazepam


Trade Name Xanax Librium, others Klonopin Tranxene, others Valium, others Paxipam Ativan Serax Antianxiety Dose (mg)* 0.250.5 TID 525 TID or QID 0.250.50 BID 7.515 BID to QID 210 BID to QID 2040 TID or QID 13 BID or TID 1030 TID or QID Relative Half-Life Shortintermediate Long Intermediate Long Long Long Shortintermediate Shortintermediate

*Dose refers to initial adult oral dose. Dosage is adjusted depending on the patients response. Doses are likewise often lower in elderly or debilitated patients.


SECTION 2 Pharmacology of the Central Nervous System

safer alternative to traditional antianxiety drugs such as benzodiazepines, especially if patients need to receive treatment for an extended period of time. Development of additional azapirones and other drugs that influence serotonin activity may continue to provide better and safer antianxiety agents in the future.

Use of Antidepressants in Anxiety

Many patients with anxiety also have symptoms of depression.47 It therefore seems reasonable to include antidepressant drugs as part of the pharmacological regimen in these patients. Hence, patients with a combination of anxiety and depression often take a traditional antianxiety agent such as a benzodiazepine along with an antidepressant.44 The pharmacology of the antidepressants is addressed in Chapter 7. Antidepressant drugs, however, might have direct anxiolytic effects. That is, certain antidepressants such as paroxetine (Paxil) or venlafaxine (Effexor) can help reduce anxiety independent of their effects on depression.1,47 These antidepressants have therefore been advocated as an alternative treatment for anxiety, especially for people who cannot tolerate the side effects of traditional anxiolytics, or who might be especially susceptible to the addictive properties of drugs like the benzodiazepines.1,9,46 Moreover, antidepressants such as paroxetine or venlafaxine are now considered effective as the primary treatment for several forms of anxiety, including generalized anxiety disorder, social phobia, and panic disorder.4,29,53 Antidepressants, either used alone or in combination with antianxiety drugs, have become an important component in the treatment of anxiety.

these drugs can decrease situational anxiety without producing sedation.27 In particular, beta blockers such as propranolol (Inderal) have been used by musicians and other performing artists to decrease cardiac palpitations, muscle tremors, hyperventilation, and other manifestations of anxiety that tend to occur before an important performance.43 Beta blockers probably exert their antianxiety effects through their ability to decrease activity in the sympathetic nervous system, that is, through their sympatholytic effects. These drugs may exert both peripheral sympatholytic effects (e.g., blockade of myocardial beta-1 receptors) as well as decreasing central sympathetic tone. In any event, beta blockers may offer a suitable alternative to decrease the effects of nervousness without a concomitant decrease in levels of alertness or motivation.43 Again, these drugs have gained popularity with performing artists as a way to blunt the symptoms of performance anxiety without actually diminishing the anticipation and excitement that is requisite for a strong performance.

Problems and Adverse Effects

Most of the problems that occur with benzodiazepine anxiolytic drugs are similar to those mentioned regarding the use of these agents as sedative-hypnotics. Sedation is still the most common side effect of anxiolytic benzodiazepines, even though this effect is not as pronounced as with their sedative-hypnotic counterparts.61 Still, even short-term use of these drugs can produce psychomotor impairment, especially during activities that require people to remain especially alert, such as driving a car.60,61 Addiction and abuse are problems with chronic benzodiazepine use, and withdrawal from these drugs can be a serious problem.36 Also, anxiety can return to, or exceed, pretreatment levels when benzodiazepines are suddenly discontinued, a problem known as rebound anxiety.1,13 The fact that chronic benzodiazepine use can cause these problems reinforces the idea that these drugs are not curative and should be used only for limited periods of time as an adjunct to other nonpharmacologic procedures such as psychologic counseling.24,45 Problems and side effects associated with buspirone include dizziness, headache, nausea, and restlessness. Antidepressants such as paroxetine and venlafaxine also produce a number of side effects (described in Chapter 7) depending on the specific agent. Nonetheless, these newer, nonbenzodiazepine

Other Antianxiety Drugs

The ideal antianxiety agent is nonaddictive, safe (i.e., relatively free from harmful side effects and potential for lethal overdose), and not associated with any sedative properties. Drugs such as meprobamate (Miltown) and barbiturates are not currently used to any great extent because they do not meet any of these criteria and are no more effective in reducing anxiety than benzodiazepines. As indicated earlier, buspirone and certain antidepressants currently offer an effective and somewhat safer method of treating anxiety, and the use of these agents has increased dramatically in recent years. Another option includes the beta-adrenergic antagonists (beta blockers, see Chapter 20) because

Chapter 6 Sedative-Hypnotic and Antianxiety Agents


anxiolytics tend to produce less sedation, and their potential for addiction is lower compared to benzodiazepines. Hence, nonbenzodiazepine drugs might be an attractive alternative, especially in patients who are prone to sedation (e.g., older adults), patients with a history of substance abuse, or people who need chronic anxiolytic treatment.

Special Consideration of Sedative-Hypnotic and Antianxiety Agents in Rehabilitation

Although these drugs are not used to directly influence the rehabilitation of musculoskeletal or other somatic disorders, the prevalence of their use in patient populations is high. Any time a patient is hospitalized for treatment of a disorder, a substantial amount of apprehension and concern exists. The foreign environment of the institution as well as a change in the individuals daily routine can understandably result in sleep disturbances.23 Likewise, older adults often have trouble sleeping, and the use of sedativehypnotic agents is common, especially in patients living in nursing homes or other facilities.8,35,41 Individuals who are involved in rehabilitation programs, both as inpatients and as outpatients, may also have a fairly high level of anxiety because of concern about their health and ability to resume normal functioning.33 Acute and chronic illnesses can create uncertainty about a patients future family and job obligations as well as doubts about his or her selfimage. The tension and anxiety produced may necessitate pharmacologic management. The administration of sedative-hypnotic and antianxiety drugs has several direct implications for the rehabilitation session. Obviously the patient will be much calmer and more relaxed after taking an antianxiety drug, thus offering the potential benefit of gaining the patients full cooperation during a physical or occupational therapy treatment. Anxiolytic benzodiazepines, for example, reach peak blood levels 2 to 4 hours after oral administration, so scheduling the rehabilitation session during that time may improve the patients participation in treatment. Of course, this rationale will backfire if the drug produces significant hypnotic effects. Therapy sessions that require the patient to actively participate in activities such as gait training or therapeutic exercise will be essentially useless and even hazardous if the patient is

extremely drowsy. Consequently, scheduling patients for certain types of rehabilitation within several hours after administration of sedative-hypnotics or sedativelike anxiolytics is counterproductive and should be avoided. Finally, benzodiazepines and other drugs used to treat sleep disorders and anxiety are often associated with falls and subsequent trauma including hip fractures, especially in older adults.15,45,60 The risk of falls is greater in people who have a history of doing so or who have other problems that would predispose them to falling (vestibular disorders, impaired vision, and so forth). Therapists can identify such people and intervene to help prevent this through balance training, environmental modifications (removing cluttered furniture, throw rugs, and so forth), and similar activities. Therapists can help plan and implement nonpharmacological interventions to help decrease anxiety and improve sleep. Interventions such as regular physical activity, massage, and various relaxation techniques may be very helpful in reducing stress levels and promoting normal sleep.38,40,56 Therapists can therefore help substitute nonpharmacological methods for traditional sedative-hypnotic and antianxiety drugs, thus improving the patients quality of life by avoiding drug-related side effects.

Sedative-hypnotic and antianxiety drugs play a prominent role in todays society. The normal pressures of daily life often result in tension and stress, which affects an individuals ability to relax or cope with stress. These problems are compounded when there is some type of illness or injury present. As would be expected, a number of patients seen in a rehabilitation setting are taking these drugs. Benzodiazepines have long been the premier agents used to treat sleep disorders and anxiety; they all share a common mechanism of action, and they potentiate the inhibitory effects of GABA in the CNS. With regard to their sedative-hypnotic effects, benzodiazepines such as flurazepam and triazolam are commonly used to promote sleep. Although these drugs are generally safer than their forerunners, they are not without their problems. Newer nonbenzodiazepine sedative-hypnotics such as zolpidem and zaleplon may also be effective in treating sleep disorders, and these newer agents may be somewhat safer than their benzodiazepine counterparts. Benzodiazepines such as diazepam (Valium)


SECTION 2 Pharmacology of the Central Nervous System

Sedative-Hypnotic Drugs
Brief History. R.S. is a 34-year-old construction worker who sustained a fracture-dislocation of the vertebral column in an automobile accident. He was admitted to an acute care facility, where a diagnosis of complete paraplegia was made at the T-12 spinal level. Surgery was performed to stabilize the vertebral column. During the next 3 weeks, his medical condition improved. At the end of 1 month, he was transferred to a rehabilitation facility to begin an intensive program of physical and occupational therapy. Rehabilitation included strengthening and range-of-motion (ROM) exercises, as well as training in wheelchair mobility, transfers, and activities of daily living (ADLs). However, upon arriving at the new institution, R.S. complained of difficulty sleeping. Flurazepam (Dalmane) was prescribed at a dosage of 20 mg administered orally each night at bedtime. Problem/Influence of Medication. During his daily rehabilitation regimen, the therapists noted that R.S.s performance and level of attentiveness were markedly poor during the morning sessions. He was excessively lethargic and drowsy, and his speech was slurred. These symptoms were present to a much greater extent than the normal slow start that occurs in some patients on wakening in the morning. The therapists also found that when ADL or mobility training was taught during the morning sessions, there was poor carryover from day to day regarding these activities. Decision/Solution. The benzodiazepine drug appeared to be producing a hangoverlike effect, which limited the patients cognitive skills during the early daily activities. Initially this problem was dealt with by reserving the early morning session for stretching and ROM activities, and then gradually moving into upper-body strengthening. Activities that required more patient learning and comprehension were done later in the morning or in the afternoon. Also, this hangoverlike problem was brought to the attention of the physician, and the hypnotic drug was ultimately switched to zolpidem (Ambien) because this is a relatively short-acting nonbenzodiazepine with a half-life of 2.6 hours (range 1.44.5 hours), compared to flurazepam (Dalmane), which is a long-acting benzodiazepine that can have a half-life of up to 74 hours (range 47100 hours) because of its active metabolites. Switching to zolpidem might also result in fewer problems (i.e., rebound insomnia) when it is time to discontinue the drug.

leave as are also used frequently to reduce anxiety, but the introduction of newer drugs such as buspirone and specific antidepressants (paroxetine, venlafaxine) have provided an effective but somewhat safer alternative for treating anxiety. Because of the potential for phys-

ical and psychologic dependence, sedative-hypnotic and antianxiety drugs should not be used indefinitely. These drugs should be prescribed judiciously as an adjunct to helping patients deal with the source of their problems.

1. Allgulander C, Bandelow B, Hollander E, et al. WCA recommendations for the long-term treatment of generalized anxiety disorder. CNS Spectr. 2003;8(suppl 1): 5361. 2. Apter JT, Allen LA. Buspirone: future directions. J Clin Psychopharmacol. 1999;19:8693. 3. Atack JR. Anxioselective compounds acting at the GABA (A) receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord. 2003;2:213232. 4. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders. World J Biol Psychiatry. 2002;3:171199. 5. Bettler B, Kaupmann K, Mosbacher J, Gassmann M. Molecular structure and physiological functions of GABA (B) receptors. Physiol Rev. 2004;84:835867.

6. Bond AJ, Wingrove J, Baylis M, Dalton J. Buspirone decreases physiological reactivity to unconditioned and conditioned aversive stimuli. Psychopharmacology. 2003;165:291295. 7. Bond AJ, Wingrove J, Valerie Curran H, Lader MH. Treatment of generalised anxiety disorder with a short course of psychological therapy combined with buspirone or placebo. J Affect Disord. 2002;72: 267271. 8. Bourne RS, Mills GH. Sleep disruption in critically ill patients pharmacological considerations. Anaesthesia. 2004;59:374384. 9. Brawman-Mintzer O. Pharmacologic treatment of generalized anxiety disorder. Psychiatr Clin North Am. 2001;24:119137. 10. Bronowska A, Les A, Chilmonczyk Z, et al. Molecular dynamics of buspirone analogues interacting with the 5-HT1A and 5-HT2A serotonin receptors. Bioorg Med Chem. 2001;9:881895.

Chapter 6 Sedative-Hypnotic and Antianxiety Agents 11. Burt DR. Reducing GABA receptors. Life Sci. 2003; 73:17411717. 12. Chilmonnczyk Z, Cybulski J, Bronowska A, Les A. Molecular modeling of buspironeserotonin receptor interactions. Acta Pol Pharm. 2000;57:281288. 13. Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry. 2004;65(suppl 5):712. 14. Costa E. From GABAA receptor diversity emerges a unified vision of GABAergic inhibition. Annu Rev Pharmacol Toxicol. 1998;38:321350. 15. Cumming RG, Le Couteur DG. Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs. 2003;17:825837. 16. Davidson JR. Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry. 2004;65(suppl 5):2933. 17. Davies M. The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci. 2003;28:263274. 18. Drake CL, Roehrs T, Roth T. Insomnia causes, consequences, and therapeutics: an overview. Depress Anxiety. 2003;18:163176. 19. Drover DR. Comparative pharmacokinetics and pharmacodynamics of short acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet. 2004;43:227238. 20. Dundar Y, Dodd S, Strobl J, et al. Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Hum Psychopharmacol. 2004;19:305 322. 21. Evers AS, Crowder CM. General anesthetics. In: Hardman JG, et al., eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 22. Fraser AD. Use and abuse of the benzodiazepines. Ther Drug Monit. 1998;20:481489. 23. Frighetto L, Marra C, Bandali S, et al. An assessment of quality of sleep and the use of drugs with sedating properties in hospitalized adult patients. Health Qual Life Outcomes. 2004;2:17. 24. Gorman JM. Treating generalized anxiety disorder. J Clin Psychiatry. 2003;64(suppl 2):2429. 25. Grunstein R. Insomnia. Diagnosis and management. Aust Fam Physician. 2002;31:9951000. 26. Hajak G, Muller WE, Wittchen HU, et al. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction. 2003;98: 13711378. 27. James IM. Practical aspects of the use of beta-blockers in anxiety states: situational anxiety. Postgrad Med J. 1984;60(suppl 2):1925. 28. Johnston GA. Medicinal chemistry and molecular pharmacology of GABA(C) receptors. Curr Top Med Chem. 2002;2:903913. 29. Kapczinski F, Lima MS, Souza JS, Schmitt R. Antidepressants for generalized anxiety disorder. Cochrane Database Syst Rev. 2003;CD003592.


30. Kitayama M, Hirota K, Kudo M, Kudo T, Ishihara H, Matsuki A. Inhibitory effects of intravenous anaesthetic agents on K ( )-evoked glutamate release from rat cerebrocortical slices. Involvement of voltage sensitive Ca (2 ) channels and GABA (A) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2002;366:246253. 31. Kumar S, Fleming RL, Morrow AL. Ethanol regulation of gammaaminobutyric acid A receptors: genomic and nongenomic mechanisms. Pharmacol Ther. 2004; 101:211226. 32. Lader MH. Implications of hypnotic flexibility on patterns of clinical use. Int J Clin Pract Suppl. 2001;116: 1419. 33. Lecrubier Y. Posttraumatic stress disorder in primary care: a hidden diagnosis. J Clin Psychiatry. 2004;65 (suppl 1):4954. 34. Lee YJ. Overview of the therapeutic management of insomnia with zolpidem. CNS Drugs. 2004; 18(suppl 1):1723; discussion 41, 4345. 35. Lenhart SE, Buysse DJ. Treatment of insomnia in hospitalized patients. Ann Pharmacother. 2001;35: 14491457. 36. Longo LP, Johnson B. Addiction: part I. Benzodiazepinesside effects, abuse risk and alternatives. Am Fam Physician. 2000;61:21212128. 37. Lydiard RB. The role of GABA in anxiety disorders. J Clin Psychiatry. 2003;64(Suppl 3):2127. 38. Mamtani R, Cimino A. A primer of complementary and alternative medicine and its relevance in the treatment of mental health problems. Psychiatr Q. 2002;73: 367381. 39. Mitler MM. Nonselective and selective benzodiazepine receptor agonistswhere are we today? Sleep. 2000;23 (suppl 1):S39S47. 40. Morgan K, Dixon S, Mathers N, et al. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use. Health Technol Assess. 2004;8: 168. 41. Nagel CL, Markie MB, Richards KC, Taylor JL. Sleep promotion in hospitalized elders. Medsurg Nurs. 2003; 12:279289. 42. Neubauer DN. Pharmacologic approaches for the treatment of chronic insomnia. Clin Cornerstone. 2003;5:1627. 43. Nies AS. Clinical pharmacology of the beta-adrenergic blockers. Med Probl Perform Art. 1986;1:2531. 44. Pary R, Matuschka PR, Lewis S, et al. Generalized anxiety disorder. South Med J. 2003;96:581586. 45. Petrovic M, Mariman A, Warie H, et al. Is there a rationale for prescription of benzodiazepines in the elderly? Review of the literature. Acta Clin Belg. 2003;58:2736. 46. Rickels K, Rynn M. Pharmacotherapy of generalized anxiety disorder. J Clin Psychiatry. 2002; 63(Suppl 14):916. 47. Rouillon F. Long term therapy of generalized anxiety disorder. Eur Psychiatry. 2004;19:96101. 48. Rudolph U. Identification of molecular substrate for the attenuation of anxiety: a step toward the development of better anti-anxiety drugs. ScientificWorld Journal. 2001;1:192193.


SECTION 2 Pharmacology of the Central Nervous System apy for persistent insomnia. Am J Psychiatry. 2002; 159:511. Sramek JJ, Zarotsky V, Cutler NR. Generalised anxiety disorder: treatment options. Drugs. 2002;62: 1635 1648. Terzano MG, Rossi M, Palomba V, Smerieri A, Parrino L. New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf. 2003;26:261282. Trevor AJ, Way WL. Sedative-hypnotic drugs. In: Katzung BG, ed. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw Hill; 2004. Vermeeren A. Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs. 2004;18: 297328. Verster JC, Volkerts ER. Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature. CNS Drug Rev. 2004;10: 4576. Wagner J, Wagner ML. Non-benzodiazepines for the treatment of insomnia. Sleep Med Rev. 2000;4: 551581. Wang JS, DeVane CL. Pharmacokinetics and drug interactions of the sedative hypnotics. Psychopharmacol Bull. 2003;37:1029.

49. Rudolph U, Mohler H. Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol. 2004;44: 475498. 50. Salzman C. Addiction to benzodiazepines. Psychiatr Q. 1998;69:251261. 51. Sanger DJ. The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs. 2004; 18(suppl 1):915; discussion 41, 4345. 52. Sanna E, Busonero F, Talani G, et al. Comparison of the effects of zaleplon, zolpidem, and triazolam at various GABA (A) receptor subtypes. Eur J Pharmacol. 2002;451:103110. 53. Sheehan DV, Mao CG. Paroxetine treatment of generalized anxiety disorder. Psychopharmacol Bull. 2003;37 (suppl 1):6475. 54. Shelton CI. Diagnosis and management of anxiety disorders. J Am Osteopath Assoc. 2004; 104(suppl 3): S2S5. 55. Sigel E. Mapping of the benzodiazepine recognition site on GABA (A) receptors. Curr Top Med Chem. 2002;2:833839. 56. Smith MT, Perlis ML, Park A, et al. Comparative meta-analysis of pharmacotherapy and behavior ther-

57. 58.


60. 61.

62. 63.


Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome

Affective disorders comprise the group of mental conditions that includes depression, bipolar syndrome (manic-depression), and several others that are characterized by a marked disturbance in a patients mood.41 Patients with an affective disorder typically present with an inappropriate disposition, feeling unreasonably sad and discouraged (major depressive disorder) or fluctuating between periods of depression and excessive excitation and elation (bipolar disorder). Because these forms of mental illness are relatively common, many rehabilitation specialists will work with patients who are receiving drug therapy for an affective disorder. Also, serious injury or illness may precipitate an episode of depression in the patient undergoing physical rehabilitation. Consequently, this chapter will discuss the pharmacologic management of affective disorders, as well as how antidepressant and antimanic drugs may influence the patient involved in physical therapy and occupational therapy. ings of sadness and despair. While a certain amount of disappointment and sadness is part of everyday life, a diagnosis of clinical depression indicates that these feelings are increased in both intensity and duration to an incapacitating extent. Depressive disorders are characterized by a general dysphoric mood (sadness, irritability, feeling down in the dumps), as well as by a general lack of interest in previously pleasurable activities. Other symptoms including anorexia, sleep disorders (either too much or too little), fatigue, lack of self-esteem, somatic complaints, and irrational guilt. Recurrent thoughts of death and suicide may also help lead to a diagnosis of depression. To initiate effective treatment, a proper diagnosis must be made; depression must not be confused with other mental disorders that also may influence mood and behavior (e.g., schizophrenia). To standardize the terminology and aid in recognizing depression, specific criteria for diagnosis has been outlined by the American Psychiatric Association.2 Depressive disorders can also be subclassified according to the type, duration, and intensity of the patients symptoms.9,41,71 For the purpose of this chapter, the term depression will be used to indicate major depressive disorder, but readers should be aware that the exact type of depression may vary somewhat from person to person. The causes of depression seem to be complex and unclear. Although a recent stressful incident, misfortune, or illness can certainly exacerbate an episode of depression, some patients may become depressed for

Clinical Picture
Depression is considered to be the most prevalent mental illness in the United States, with approximately 15 percent of adults experiencing major depression at some point in their life.73 Likewise, as many as 10 percent of Americans may experience major depression over a 1-year period.43 In this sense, depression is a form of mental illness characterized by intense feel-


SECTION 2 Pharmacology of the Central Nervous System

no apparent reason. The role of genetic factors in depression has been explored but remains uncertain. Over the past few decades, it has been suggested that a central nervous system (CNS) neurochemical imbalance may be the underlying feature in depression, as well as in other forms of mental illness. The importance of these findings as related to pharmacologic treatment will be discussed later. However, factors responsible for initiating these changes in CNS function are unclear. Depression is undoubtedly caused by the complex interaction of a number of genetic, environmental, and biochemical factors.18,38,46,57 Treatment of depression is essential in minimizing the disruptive influence that this disease has on the patients quality of life, and on his or her relationship with their family and job. Procedures ranging from psychotherapy to electroconvulsive treatment can be prescribed, depending on the severity and type. Drug treatment plays a major role in alleviating and preventing the occurrence of major depression, and this form of therapy is presented here.

Pathophysiology of Depression
It appears that depression is related to a disturbance in CNS neurotransmission involving certain chemicals know as amine neurotransmitters. These transmitters include 5-hydroxytryptamine (serotonin), norepi-

nephrine, and dopamine. Amine neurotransmitters are found in many areas of the brain, and are important in controlling many aspects of mood and behavior. However, the exact problem in CNS amine neurotransmission remains a subject of much debate. One leading theory is that depression may be caused by an increased sensitivity of the presynaptic or postsynaptic receptors for these transmitters. That is, the neurochemistry of the brain has been changed in some way to make the amine receptors more sensitive to their respective amine neurotransmitters (norepinephrine, serotonin, and to a lesser extent, dopamine).21 This theory is based primarily on the finding that antidepressant drugs prolong the activity of amine neurotransmission in the brain, thereby causing a compensatory decrease in the sensitivity of the amine receptors.21,47 The idea that depression is associated with changes in amine receptor sensitivity is summarized in Figure 71. For reasons that are still unclear, depression might occur because of an increase in postsynaptic receptor sensitivity to amine neurotransmitters, particularly norepinephrine and serotonin.4 Antidepressant drugs increase amine transmission by a variety of methods, thereby bringing about overstimulation of the postsynaptic receptor. (The exact method by which these drugs increase amine stimulation is discussed later in this chapter.) Overstimulation

1. Depression: receptor "supersensitivity" to amine neurotransmitters

2. Antidepressants: enhance stimulation of postsynaptic and presynaptic receptors

3. Down-regulations: receptor sensitivity decreases

FIGURE 71 Theoretic basis for the mechanism and treatment of depression. Functionally active receptor sites are indicated by an *. Depression is believed to be initiated by increased postsynaptic or presynaptic receptor sensitivity. Drugs that enhance stimulation of these receptors ultimately lead to receptor down-regulation, thus resolving the depression (see text for details).

Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome


of the postsynaptic receptor then leads to a compensatory down-regulation and decreased sensitivity of the receptor. As discussed in Chapter 4, this down-regulation is a normal response to overstimulation by either endogenous or exogenous agonists. As receptor sensitivity decreases, the clinical symptoms of depression might be resolved. On the other hand, it has been suggested that the primary problem in depression is an increased sensitivity to receptors that are located on the presynaptic terminals of amine synapses.54 These presynaptic autoreceptors normally regulate and limit the release of amine transmitters, such as norepinephrine or serotonin, from the presynaptic terminal. Increasing their sensitivity could result in a relative lack of adequate neurotransmitter release at these synapses. By causing overstimulation of these presynaptic receptors, antidepressant drugs could eventually normalize their sensitivity and help reestablish proper control and regulation of these amine synapses.54 It must be emphasized that it is difficult to prove the neurochemical changes that underlie depression, and the way that antidepressant drugs help resolve depression remains theoretical at present. Still, certain aspects of drug therapy tend to support the amine hypothesis and the putative changes in receptor sensitivity induced by drug therapy. For instance, there is usually a time lag of approximately 2 to 4 weeks before antidepressant drugs begin to work.54 This latency period would be necessary for a compensatory change in receptor sensitivity to take place after drug therapy is initiated.54 Still, the exact neurochemical changes in depression are difficult to determine, and probably involve other neurotransmitters and receptors. For example, high levels of glucocorticoids, such as cortisol, are found in the bloodstream of certain people with depression.15 This makes sense because cortisol is often released from the adrenal cortex in response to stress, and prolonged or severe stress can be a precipitating factor in certain forms of depression (see Chapter 28 for a description of cortisol production).40,68 Apparently, excess glucocorticoid levels overstimulate glucocorticoid receptors in the brain, bringing about a compensatory decrease in the sensitivity and responsiveness of these receptors.7 The decreased responsiveness of these glucocorticoid receptors is somehow related to the dysfunction in serotonin neurotransmission described above.40 The relationship between glucocorticoid receptor sensitivity and dysfunctional serotonin activity is not completely understood, and the exact way that these systems interact has not been

determined.59 Nonetheless, it is apparent that stress hormones such as cortisol can play a role in the pathogenesis of depression, and research is currently underway to discover how antidepressant medications can help normalize glucocorticoid responsiveness in certain types of the disorder.7 Hence, complex neurochemical changes seem to occur in certain areas of the brain in people with depression, and these changes may vary depending on each person and the specific type of depression. Likewise, changes in other brain chemicalssuch as brainderived tropic factor, gamma-aminobutyric acid (GABA), substance P, glutamate, and cyclic adenosine monophosphate (cAMP) response element may also play a role in the pathophysiology of depression.1,4,36,56 Changes in brain chemistry may be associated with altered neuronal structure and plasticity, and changes in cellular growth and hippocampus volume have been reported in people with depression.42,50,66 Future research will continue to clarify the exact cellular and subcellular events that occur during depression, and how these events can be resolved pharmacologically. It is apparent, however, that current drug therapy is focused on modifying one or more receptor populations at brain synapses that use amine transmitters. These drugs are discussed here.

Antidepressant Drugs
The drugs that are currently used to treat depression are grouped into several categories, according to chemical or functional criteria. These categories consist of the tricyclics, monoamine oxidase (MAO) inhibitors, and second-generation drugs (Table 71). All three groups attempt to increase aminergic transmission, but by different mechanisms (Fig 72). Sympathomimetic stimulants such as the amphetamine drugs were also used on a limited basis to treat depression, but the powerful CNS excitation produced by amphetaminelike drugs and the potential for addiction and overdose have essentially eliminated their use as antidepressants. The pharmacologic effects of the primary antidepressant drug categories are discussed below. Tricyclics. Drugs in this category share a common three-ring chemical structure (hence the name tricyclic). These drugs work by blocking the reuptake of amine neurotransmitters into the presynaptic terminal.61,67 Actively transporting amine neurotransmitters back into the presynaptic terminal is the method by which most (50 to 80 percent) of the released transmitter is removed from the synaptic cleft. By blocking reuptake, tricyclics allow the released amines to


SECTION 2 Pharmacology of the Central Nervous System

Table 71
Generic Name Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Nortriptyline Protriptyline Trimipramine


Trade Name Elavil, Endep, others Asendin Anafranil Norpramin Sinequan Norfranil, Tofranil, others Aventyl, Pamelor Vivactil Surmontil Initial Adult Dose (mg/day) Tricyclics 50100 100150 75 100200 75 75200 75100 1540 75 Monoamine oxidase (MAO) inhibitors 300 600 300 300 300 300 150 60 300 Prescribing Limits* (mg/day)

Isocarboxazid Phenelzine Tranylcypromine

Marplan Nardil Parnate

20 45 30 Second-generation agents

60 90 60

Bupropion Citalopram Escitalopram Fluoxetine Fluvoxamine Maprotiline Mirtazapine Nefazodone Paroxetine Sertraline Trazodone Venlafaxine

Wellbutrin Celexa Lexapro Prozac Luvox Ludiomil Remeron Serzone Paxil Zoloft Desyrel Effexor

150 20 10 20 50 2575 15 200 20 50 150 75

400 60 20 80 300 225 45 600 50 200 600 375

*Upper limits reflect dosages administered to patients with severe depression who are being treated as inpatients.

Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome


Presynaptic terminal Breakdown Storage MAO MAO Inhibitors (inhibit breakdown)


Reuptake Tricyclics & Second-generation drugs (inhibit reuptake)

Postsynaptic neuron

FIGURE 72 Effects of antidepressant drugs on amine synapses. All three types of drugs tend to increase the presence of amine transmitters (norepinephrine, dopamine, serotonin) in the synaptic cleft. Increased transmitter stimulation leads to postsynaptic receptor down-regulation/desensitization.

remain in the cleft and continue to exert their effects. The prolonged stimulation of these neurotransmitters (especially norepinephrine) leads to the compensatory decrease in receptor sensitivity, which ultimately leads to a decrease in depression. In the past, tricyclic drugs such as amitriptyline and nortriptyline were the most commonly used antidepressants and were the standard against which other antidepressants were measured.30 The use of tricyclic drugs as the initial treatment of depression has diminished somewhat in favor of some of the newer second-generation drugs, which may have more favorable side-effect profiles. Tricyclic agents, nonetheless, remain an important component in the management of depressive disorders, especially in more severe forms of depression that fail to respond to other antidepressants.6,53 Monoamine Oxidase Inhibitors. Monoamine oxidase (MAO) is an enzyme that is located at amine synapses and helps remove released transmitters through enzymatic destruction. Drugs that inhibit this enzyme allow more of the transmitter to remain in the synaptic cleft and continue to exert an effect.74 As with

the tricyclics, MAO inhibitors directly increase activity at amine synapses, which can bring about changes in the activity and sensitivity of receptors at this synapse. MAO inhibitors are not usually the drugs of choice in depression, but they may be helpful if patients do not respond to other agents (tricyclics, second-generation drugs), or if other antidepressants produce intolerable side effects. The MAO enzyme exists in two primary forms or subtypes: MAO type A and MAO type B.4 These two subtypes are differentiated according to their ability to degrade specific amines and according to the ability of various drugs to inhibit one or both subtypes of the MAO enzyme. Preliminary evidence suggests that selective inhibition of MAO type A may be desirable in treating depression,4 whereas inhibition of MAO type B may be more important in prolonging the effects of dopamine in Parkinson disease (see Chapter 10). Regardless, the MAO inhibitors currently used as antidepressants are relatively nonselective, meaning that they inhibit MAO A and MAO B fairly equally. Development of new MAO inhibitors may produce agents that are more selective for the MAO A subtype


SECTION 2 Pharmacology of the Central Nervous System

and may therefore produce better antidepressant effects with fewer side effects.4 Second-Generation Antidepressants. Because of the limitations of first-generation drugs such as the tricyclics and MAO inhibitors, a number of diverse compounds have been developed and continue to be evaluated for their antidepressant effects. There is some evidence that certain second-generation drugs are more effective in treating specific depressive symptoms in some patients, but the newer agents have not been proven to be categorically more effective than the older drugs.12,48,70 The newer agents, however, tend to have a lower incidence of side effects such as cardiovascular problems, sedation, and so forth. Hence, these newer drugs may be better-tolerated and provide better long-term management of depression because of improved patient satisfaction and adherence to drug therapy.58 Newer antidepressants are chemically diverse, but most work by mechanisms similar to tricyclic drugs; that is, they block reuptake of norepinephrine and other monoamines. Hence, these drugs appear to exert their beneficial effects by bringing about a receptor sensitivity decrease, which seems to be the common denominator of antidepressant drugs action. The second-generation drugs and their proposed mechanisms of action are summarized in Table 72. In addition, certain second-generation drugs are distinguished by their ability to selectively influence specific monoamines rather than all the amine transmitters simultaneously. Subcategories of these selective drugs are discussed below. Selective serotonin reuptake inhibitors. Certain second-generation drugs have received attention because of their ability to selectively block the reuptake of 5-hydroxytryptamine (serotonin). Fluoxetine (Prozac) and similar agents (citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, see Table 72) are functionally grouped together as selective serotonin reuptake inhibitors (SSRIs).54,64 This distinguishes them from the tricyclics, MAO inhibitors, and other second-generation drugs because these other drugs tend to be nonselective in their effect on amine neurotransmitters and block the reuptake of norepinephrine and dopamine, as well as serotonin. The primary advantage of the SSRIs is that they produce fewer and less bothersome side effects than their nonselective counterparts. This improved side-effect profile can be very helpful in the long-term management of depression because patients may tolerate these drugs better and be more willing to take their medication on a

regular basis.58 SSRIs may also be less toxic during overdose than more traditional antidepressants such as the tricyclics.64,72 These serotonin selective drugs have therefore become the antidepressant drugs of choice for many patients, and are often prescribed as the initial method of treatment in people who are depressed.64 Other selective drugs. Drugs that are relatively selective for other types of monoamines are also administered as possible antidepressants. Reboxetine, for example, is a relatively new agent that selectively inhibits transmitter reuptake at norepinephrine synapses.34,55 There is likewise an emerging group of drugs, such as venlafaxine, that selectively decrease serotonin and norepinephrine reuptake without an appreciable effect of dopamine synapses.31 These drugs are known as serotonin/norepinephrine reuptake inhibitors (SNRIs), and they may be more effective than other agents in resolving depression, especially in resistant cases or in people with severe depression.19,33,69 There is also some evidence that SNRIs such as venlafaxine and mirtazapine might take effect more quickly than traditional drugs such as the tricyclics and SSRIs.11,19 The development of SNRIs and various other selective drugsincluding SSRIshas opened new opportunities for the optimal management of depression. Future studies will undoubtedly shed light on how these more selective agents can be best used to treat specific depressive symptoms and types of depression.

Antidepressants are usually administered orally. Dosages vary depending not only on each drug but also on the individual patient. Initial dosages generally start out relatively low and are increased slowly within the therapeutic range until beneficial effects are observed. Distribution within the body also varies with each type of antidepressant, but all eventually reach the brain to exert their effects. Metabolism takes place primarily in the liver, and metabolites of several drugs continue to show significant antidepressant activity. This fact may be responsible for prolonging the effects of the drug, even after it has undergone hepatic biotransformation. Elimination takes place by biotransformation and renal excretion.

Problems and Adverse Effects

Tricyclics. A major problem with the tricyclic antidepressants is sedation (Table 73). Although a

Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome


Table 72
Drug Citalopram (Celexa)


Mechanism (Amine selectivity) Strong, selective inhibition of serotonin reuptake Advantages Low incidence of sedation and anticholinergic effects; does not cause orthostatic hypotension or cardiac arrhythmias Similar to citalopram Disadvantages May cause sexual dysfunction (decreased libido, impotence)

Selective serotonin reuptake inhibitors

Escitalopram (Lexapro) Fluoxetine (Prozac)

Strong, selective inhibition of serotonin reuptake Moderate, selective inhibition of serotonin reuptake

Similar to citalopram

No sedative, anticholinergic, or cardiovascular side effects; helpful in obsessive-compulsive disorder Similar to fluoxetine

May cause anxiety, nausea, insomnia; long half-life can lead to accumulation

Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft)

Strong, selective inhibition of serotonin reuptake Strong, selective inhibition of serotonin reuptake Strong, selective inhibition of serotonin reuptake

Similar to fluoxetine

Similar to citalopram

Similar to citalopram

Similar to fluoxetine

Similar to fluoxetine

Other second-generation agents Primarily inhibits dopamine Bupropion reuptake; little effect on (Wellbutrin, Zyban) norepinephrine or serotonin Low sedative, anticholinergic, and cardiovascular side effects; also used as an intervention to quit cigarette smoking Sedating: useful in agitation May cause overstimulation (insomnia, tremor) and induce psychotic symptoms

Maprotiline (Ludiomil) Mirtazapine (Remeron)

Moderate inhibition of norepinephrine reuptake Exact mechanism unclear; may increase norepinephrine and serotonin activity by blocking inhibitory presynaptic autoreceptors Slight inhibition of serotonin and norepinephrine reuptake; may also block CNS serotonin receptors

Possibility of seizures; overdoses lethal; long half-life May cause agitation, anxiety, other mood changes

Low incidence of sedative, anticholinergic, and cardiovascular side effects

Nefazodone (Serzone)

Sedating: useful in agitation

May cause orthostatic hypotension because of antagonistic effect on vascular alpha-1 receptors
(Continued on following page)


SECTION 2 Pharmacology of the Central Nervous System

Table 72
Drug Trazodone (Desyrel)


Mechanism (Amineselectivity) Slight inhibition of serotonin reuptake Advantages Sedating: useful in agitation; lower relative risk of overdose Disadvantages May cause orthostatic hypotension (similar to nefazodone); serious problems related to priapism may also occur in men May cause hypertension

Venlafaxine (Effexor)

Strong inhibition of norepinephrine and serotonin reuptake

Low risk of orthostatic hypotension, sedation, and anticholinergic side effects

certain degree of sedation may be desirable in some patients who are agitated and depressed, feelings of lethargy and sluggishness may impair patient adherence to drug therapy and result in a failure to take medication. A second major problem is that these drugs tend to have significant anticholinergic properties; that is, they act as if they are blocking certain central and peripheral acetylcholine receptors (see Table 73). Impairment of central acetylcholine transmission may cause confusion and delirium. The peripheral anticholinergic properties produce a variety of symptoms including dry mouth, constipation, urinary retention, and tachycardia. Other cardiovascular problems include arrhythmias and orthostatic hypotension, with the latter being particularly common in elderly patients. Finally, tricyclics have the highest potential for fatal overdose from an antidepressant.62,72 This fact leads to a serious problem when one considers the risk of suicide among depressed patients. These drugs should be used cautiously in patients who have suicidal thoughts or a history of suicidal behaviors. MAO Inhibitors. In contrast to the tricyclics, MAO inhibitors tend to produce CNS excitation, which can result in restlessness, irritability, agitation, and sleep loss. These drugs also produce some central and peripheral anticholinergic effects (e.g., tremor, confusion, dry mouth, urinary retention), but these effects tend to occur in a lesser extent than with the tricyclics (see Table 73). Because of the systemic MAO inhibition, excess activity at peripheral sympathetic adrenergic terminals may cause a profound increase in blood pressure, leading to a hypertensive crisis. This situation is exacerbated if other drugs that increase sympathetic nervous activity are being taken

concurrently. Also, there is a distinct interaction between the MAO inhibitors and certain foods such as fermented cheese and wines.76 These fermented foods contain tyramine, which stimulates the release of endogenous epinephrine and norepinephrine (the socalled cheese effect). The additive effect of increased catecholamine release (because of the ingested tyramine) and decreased catecholamine breakdown (because of MAO inhibition) can lead to excessive catecholamine levels and a hypertensive crisis.76 Second-Generation Drugs. The type and severity of side effects associated with newer antidepressants varies according to the specific drug in use. SSRIs and SNRIs, for example, generally produce less sedation, anticholinergic effects, and cardiovascular effects than the tricyclics, MAO inhibitors, and other secondgeneration drugs.17 These newer drugs, however, are not devoid of side effects, and these agents often produce more gastrointestinal problems and insomnia than other antidepressants. Also, drugs that cause an excessive increase of serotonin activity in the brain may cause serotonin syndrome, which is characterized by sweating, shivering, movement disorders (severe restlessness, dystonias, dyskinesias), muscle fasciculations, and other neuromuscular symptoms.22,25 These symptoms typically disappear if the drug is discontinued, but they should be identified early or this syndrome could progress to seizures and coma.25 Advantages and disadvantages of common second-generation drugs are listed in Table 72, and comparison of these drugs to the tricyclics and MAO inhibitors is summarized in Table 73. Various factors, including potential side effects, are considered when selecting one of these drugs, and selection of the best drug must be done on a patient-by-patient basis.

Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome


Table 73
Drug Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Nortriptyline Protriptyline Trimipramine


Sedation Anticholinergic Effects Orthostatic Hypotension Cardiac Arrhythmias Seizures

Tricyclic drugs

Monoamine oxidase (MAO) inhibitors Phenelzine Tranylcypromine Second-generation drugs Bupropion Citalopram Fluoxetine Fluvoxamine Maprotiline Mirtazapine Nefazodone Paroxetine Sertraline Trazodone Venlafaxine 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

*Zero denotes no side effect, a very low incidence, a low incidence, a moderate incidence, and a high incidence. Adapted from Kando, et al. Depressive disorders. In: DiPiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill; 2002:1250, with permission.


SECTION 2 Pharmacology of the Central Nervous System

Use of Antidepressants in Chronic Pain

Many chronic pain syndromes (neuropathic pain, fibromyalgia, chronic low back pain, and so forth) can be treated more effectively if antidepressants are included in the treatment regimen.45,52,65 In particular, certain tricyclic agents such as amitriptyline, nortriptyline, doxepin, and desipramine: may help provide better pain relief when used along with traditional analgesic medications or, in some cases, when these tricyclic drugs are used alone.45,60 Some studies attribute this effect to the fact that clinical depression is present in many patients with chronic pain; administering antidepressants will help provide optimal care by resolving the depressive symptoms.3,14 There is considerable evidence, however, that antidepressants will help patients with chronic pain even if no symptoms of depression are present. That is, improvements in pain have been noted even when there has been no observed effect on the patients mood. As indicated earlier, these drugs have the ability to modulate the influence of serotonin and other CNS monoamine neurotransmitters, and their effects on chronic pain may be related to the influence on monoamine transmission in critical pain pathways in the brain.13,24,45 For the most part, however, the exact way that antidepressants affect pain perception remains unknown. Hence, there is little doubt that antidepressants may be useful as an adjunct in the treatment of patients with chronic pain. Traditional tricyclic medications such as amitriptyline and nortriptyline are often considered the drugs of choice for chronic pain.52 Newer drugs such as the SSRIs (e.g., paroxetine) and SNRIs (e.g., venlafaxine) might also be considered for some patients with fibromyalgia, neuropathies, and other forms of chronic pain.29 Future research should help clarify how specific antidepressants can be used most effectively as part of a comprehensive regimen for treating various types of chronic pain.

associated with mood swings from one extreme (mania) to the other (depression).10 Manic episodes are characterized by euphoria, hyperactivity, and talkativeness, and depressive episodes are similar to those described previously. Approximately 10 percent of all patients with depression are considered to exhibit bipolar syndrome.10 As in unipolar depression, the exact causes of bipolar disorder are unknown. One theory is that genetic and environmental factors conspire to increase norepinephrine and possibly serotonin influence in the brain.23 This increase in neurotransmitter activity appears to be responsible for the manic episodes of this disorder. The subsequent depression may simply be a rebound from the general excitement of the manic episode. The exact cause of bipolar disorder is not clear; however, the manic episode of this condition may also be caused by neuroendocrine factors, an imbalance in cations such as sodium and calcium, or changes in the cellular and subcellular responses in specific brain neurons.10,23 In any event, the treatment of bipolar disorder focuses on preventing the start of these pendulumlike mood swings by preventing the manic episodes. Hence, drugs used to treat manicdepression are really antimanic drugs. The primary form of drug treatment consists of lithium salts (i.e., lithium carbonate, lithium citrate).27,44 In addition, lithium is a useful adjunct to other antidepressant drugs in treatment-resistant unipolar depression.16,28

Lithium (Li ) is a monovalent cation included in the alkali metal group. Because of its small size (molecular weight 7) and single positive charge, lithium may influence neural excitability by competing with other cations including sodium, potassium, and calcium.5 The exact way that lithium helps stabilize mood, however, is not known.32 Several theories have been proposed, and lithium has been shown to produce several neurochemical effects that could contribute to its antimanic properties. In particular, lithium may stabilize neuronal excitability by decreasing the sensitivity of certain postsynaptic receptors and by uncoupling these receptors from their subcellular second-messenger systems.5,10 For example, studies have shown that lithium can diminish the function of cAMP and other secondmessenger systems that are normally stimulated by norepinephrine.5,10 Lithium has also been shown to inhibit certain intracellular enzymes such as protein kinase C, glycogen synthetase kinase3-beta, and inosi-

Treatment of Bipolar Disorder: Antimanic Drugs

Bipolar Disorder
The form of depression discussed previously is often referred to as major depressive disorder or unipolar depression, in contrast to bipolar or manic-depressive disorder. As these terms imply, bipolar syndrome is

Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome


tol monophosphatase, which may help account for decreased neuronal excitation and desensitization.8,10,35 In addition, lithium has been shown to directly decrease the release of certain amine neurotransmitters (norepinephrine and dopamine) and to increase the effects of other transmitters (serotonin, acetylcholine, and GABA).23 Obviously, lithium has the potential to influence synaptic function and neural excitability in many ways. Exactly how this drug is able to stabilize mood and prevent the manic episodes associated with bipolar disorder remains to be determined.5,32

Absorption and Distribution

Lithium is readily absorbed from the gastrointestinal tract and completely distributed throughout all the tissues in the body. During an acute manic episode, achieving blood serum concentrations between 1.0 and 1.4 mEq/L is desirable. Maintenance doses are somewhat lower, and serum concentrations that range from 0.5 to 1.3 mEq/L are optimal.

Side effects are frequent with lithium, and the degree and type depends on the amount of lithium in the bloodstream. As Table 74 indicates, some side effects are present even when serum levels are within the therapeutic range.23 However, toxic side effects become more apparent when serum concentrations reach 1.5 mEq/L, and become severe when serum levels exceed 3.0 mEq/L.23 Progressive accumulation of lithium can lead to seizures, coma, and even death. Consequently, clinicians with patients receiving lithium should be aware of any changes in behavior that might indicate that this drug is reaching toxic levels. These changes can usually be resolved by adjusting the dosage or using a sustained-release form of lithium.27 Also, serum titers of lithium should be monitored periodically to ensure that blood levels remain within the therapeutic range.27

Other Drugs Used in Bipolar Disorder

Although lithium remains the cornerstone of treatment for bipolar disorder, it is now recognized that other agents may be helpful, especially during manic episodes. In particular, antiseizure medications such as carbamazepine, valproic acid, gabapentin, and lamotrigine may help stabilize mood and limit manic symptoms.20,26,49 Antipsychotic medications, including the newer agents such as clozapine and resperidone (see Chapter 8), may also be helpful as antimanic drugs.63,75 Antiseizure and antipsychotic drugs are believed to be helpful because they act directly on CNS neurons to

Problems and Adverse Effects of Lithium

A major problem with lithium use is the danger of accumulation within the body.27 Lithium is not metabolized, and drug elimination takes place almost exclusively through excretion in the urine. Consequently, lithium has a tendency to accumulate in the body, and toxic levels can frequently be reached during administration.

Table 74


Moderate (1.53.0 mEq/L) Confusion Lethargy Ataxia Dysarthria Nystagmus Emesis Increased deep tendon reflexes Increased tremor Muscle fasciculations Severe (Above 3.0 mEq/L) Choreoathetoid movements Seizures Respiratory complications Coma Death

Mild (Below 1.5 mEq/L) Fine hand tremor (resting) Gastrointestinal upset Muscle weakness Fatigue Problems with memory and concentration

Adapted from: Fankhauser, pp 12801281,23 with permission.


SECTION 2 Pharmacology of the Central Nervous System

help prevent the neuronal excitation that seems to precipitate manic symptoms.10 (Details about the pharmacology of antipsychotic and antiseizure drugs are addressed in Chapters 8 and 9, respectively.) Hence, these drugs can be used initially, along with lithium, to decrease manic mood swings, or to simply stabilize

mood at baseline levels and to prevent the mood swings that characterize bipolar disorder. These additional drugs may be discontinued when the mood is stabilized, or they may be administered alone or with lithium treatment as maintenance therapy in the longterm treatment of bipolar disorder.28,39,51

Special Concerns in Rehabilitation Patients

Some amount of depression is certain to be present as a result of a catastrophic injury or illness. Patients receiving physical therapy and occupational therapy for any number of acute or chronic illnesses may be taking antidepressants in order to improve their mood and general well-being. Of course, therapists working in a psychiatric facility will deal with many patients taking antidepressant drugs, and severe depression may be the primary reason the patient is institutionalized in the first place. However, these drugs are also frequently prescribed to patients with a spinal cord injury, stroke, severe burn, multiple sclerosis, amputation, and so on. Therapists must realize that adequate treatment of depression is a very difficult clinical task. Even with optimal pharmacologic and psychologic intervention, it is estimated that up to one third of patients with depression may not adequately respond.4 Depression is a very serious and complex psychological disorder, and the effects of drug treatment vary greatly from individual to individual. It is therefore imperative that the physician and other health care professionals work closely with the patient and the patients family to find the drug that produces optimal results with a minimum of side effects. Again, this task is complicated by many issues including the complex interplay of factors causing depression in each patient and their rather unpredictable response to each type of antidepressant. With regard to the impact of antidepressant and antimanic agents on the rehabilitation process, these drugs can be extremely beneficial in helping to improve a patients outlook. The patient may become more optimistic regarding the future and may assume a more active role and interest in the rehabilitation process. This behavior can be invaluable in increasing patient cooperation and improving compliance with rehabilitation goals. However, certain side effects can be somewhat troublesome during rehabilitation treatments. Sedation, lethargy, and muscle weakness can occur with the tricyclics and lithium, which can present a problem if the patients active cooperation is required. Other unpleasant side effects, such as nausea and vomiting, can also be disturbing during treatments. A more common and potentially more serious problem is the orthostatic hypotension that occurs predominantly with the tricyclics. This hypotension can cause syncope and subsequent injury if patients fall during gait training. Conversely, MAO inhibitors can increase blood pressure, and care should be taken to avoid a hypertensive crisis, especially during therapy sessions that tend to increase blood pressure (e.g., certain forms of exercise). Hence, patients should also be monitored regularly to detect an increase or decrease in blood pressure depending on the drug and the patient. Finally, rehabilitation specialists should remember that some improvement in mood may occur within 2 weeks after beginning antidepressant drug treatment, but that these agents must often be administered for 1 month or more before an appreciable improvement in symptoms occurs.4 During this period, drug therapy may actually precipitate an increase in depression, including increased thoughts of suicide.37 Rehabilitation specialists should keep alert for any signs that a patient is becoming more depressed and possibly suicidal, especially during the first few weeks after antidepressant drug therapy is initiated.

Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome


Antidepressant Drugs
Brief History. J.G., a 71-year-old retired pharmacist, was admitted to the hospital with a chief complaint of an inability to move his right arm and leg. He was also unable to speak at the time of admission. The clinical impression was right hemiplegia caused by left-middle cerebral artery thrombosis. The patient also had a history of hypertension and had been taking cardiac beta blockers for several years. J.G.s medical condition stabilized, and the third day after admission he was seen for the first time by a physical therapist. Speech and occupational therapy were also soon initiated. The patients condition improved rapidly, and motor function began to return in the right side. Balance and gross motor skills increased until he could transfer from his wheelchair to his bed with minimal assistance, and gait training activities were being initiated. J.G. was able to comprehend verbal commands, but his speech remained markedly slurred and difficult to understand. During his first 2 weeks in the hospital, J.G. showed signs of severe depression. Symptoms increased until cooperation with the rehabilitation and nursing staff was being compromised. Imipramine (Tofranil) was prescribed at a dosage of 150 mg/day. Problem/Influence of Medication. Imipramine is a tricyclic antidepressant, and these drugs are known to produce orthostatic hypotension during the initial stages of drug therapy. Since the patient is expressively aphasic, he will have trouble telling the therapist that he feels dizzy or faint. Also, the cardiac beta blockers will blunt any compensatory increase in cardiac output if blood pressure drops during postural changes. Decision/Solution. The therapist decided to place the patient on the tilt table for the first day after imipramine was started and to monitor blood pressure regularly. While the patient was on the tilt table, weight shifting and upperextremity facilitation activities were performed. The patient tolerated this well, so the therapist had him resume ambulation activities using the parallel bars on the following day. With the patient standing inside the bars, the therapist carefully watched for any subjective signs of dizziness or syncope in the patient (i.e., facial pallor, inability to follow instructions). Standing bouts were also limited in duration. By the third day, ambulation training continued with the patient outside the parallel bars, but the therapist made a point of having the patients wheelchair close at hand in case the patient began to appear faint. These precautions of careful observation and short, controlled bouts of ambulation were continued throughout the remainder of the patients hospital stay, and no incident of orthostatic hypotension was observed during physical therapy.

Affective disorders such as depression and manicdepression are found frequently in the general population as well as in rehabilitation patients. Drugs commonly prescribed in the treatment of (unipolar) depression include the tricyclics and MAO inhibitors as well as the newer second-generation antidepressants. Lithium is the drug of choice for treating bipolar disorder, or manic-depression. All of these drugs

seem to exert their effects by modifying CNS synaptic transmission and receptor sensitivity in amine pathways. The exact manner in which these drugs affect synaptic activity has shed some light on the possible neuronal changes that underlie these forms of mental illness. Antidepressant and antimanic drugs can improve the patients attitude and compliance during rehabilitation, but therapists should be aware that certain side effects may alter the patients physical and mental behavior.

1. Adell A. Antidepressant properties of substance P antagonists: relationship to monoaminergic mechanisms? Curr Drug Targets CNS Neurol Disord. 2004; 3:113121. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental DisordersRevised. 4th ed. Washington, DC: American Psychiatric Association; 1994. 3. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163:24332445.

4. Baldessarini RJ. Drugs and the treatment of psychiatric disorders: depression and anxiety disorders. In: Hardman JG, et al., eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 5. Baldessarini RJ, Tarazi FI. Drugs and the treatment of psychiatric disorders: psychosis and mania. In: Hardman JG, et al., eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 6. Barbui C, Guaiana G, Hotopf M. Amitriptyline for inpatients and SSRIs for outpatients with depression?


SECTION 2 Pharmacology of the Central Nervous System Systematic review and meta-regression analysis. Pharmacopsychiatry. 2004;37:9397. Barden N. Implication of the hypothalamic-pituitary adrenal axis in the physiopathology of depression. J Psychiatry Neurosci. 2004;29:185193. Bauer M, Alda M, Priller J, Young LT; International Group for the Study of Lithium Treated Patients (IGSLI). Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders. Pharmacopsychiatry. 2003;36(suppl 3):S250S254. Bauer M, Whybrow PC, Angst J, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 2: Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World J Biol Psychiatry. 2002;3:6986. Belmaker RH. Bipolar disorder. N Engl J Med. 2004;351:476486. Benkert O, Muller M, Szegedi A. An overview of the clinical efficacy of mirtazapine. Hum Psychopharmacol. 2002;17(suppl 1):S23S26. Blier P. The pharmacology of putative early-onset antidepressant strategies. Eur Neuropsychopharmacol. 2003;13:5766. Blier P, Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. J Psychiatry Neurosci. 2001;26:3743. Briley M. New hope in the treatment of painful symptoms in depression. Curr Opin Investig Drugs. 2003;4:4245. Brown ES, Varghese FP, McEwen BS. Association of depression with medical illness: does cortisol play a role? Biol Psychiatry. 2004;55:19. Bschor T, Lewitzka U, Sasse J, et al. Lithium augmentation in treatment-resistant depression: clinical evidence, serotonergic and endocrine mechanisms. Pharmacopsychiatry. 2003;36(suppl 3):S230S234. Cassano P, Fava M. Tolerability issues during longterm treatment with antidepressants. Ann Clin Psychiatry. 2004;16:1525. Charney DS, Manji HK. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE. 2004;2004(225):re5. Deakin B, Dursun S. Optimizing antidepressant treatment: efficacy and tolerability. Int Clin Psychopharmacol. 2002;17(suppl 1):S13S24. Dunner DL. Drug interactions of lithium and other antimanic/mood stabilizing medications. J Clin Psychiatry. 2003;64(suppl 5):3843. Elhwuegi AS. Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:435451. Ener RA, Meglathery SB, Van Decker WA, Gallagher RM. Serotonin syndrome and other serotonergic disorders. Pain Med. 2003;4:6374. Fankhauser MP. Bipolar disorder. In: DiPiro JT, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill; 2002. 24. Fava M. The role of the serotonergic and noradrenergic neurotransmitter systems in the treatment of psychological and physical symptoms of depression. J Clin Psychiatry. 2003;64(suppl 13):2629. 25. Finfgeld DL. Serotonin syndrome and the use of SSRIs. J Psychosoc Nurs Ment Health Serv. 2004; 42:1620. 26. Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM. Lamotrigine: a review of its use in bipolar disorder. Drugs. 2003;63:20292050. 27. Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment. J Clin Psychiatry. 2002;63(suppl 10):512. 28. Goodwin FK. Rationale for using lithium in combination with other mood stabilizers in the management of bipolar disorder. J Clin Psychiatry. 2003;64(suppl 5):1824. 29. Grothe DR, Scheckner B, Albano D. Treatment of pain syndromes with venlafaxine. Pharmacotherapy. 2004;24:621629. 30. Guaiana G, Barbui C, Hotopf M. Amitriptyline versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev. 2003;CD004186. 31. Gupta RK, Tiller JW, Burrows GD. Dual action antidepressants and some important considerations. Aust N Z J Psychiatry. 2003;37:190195. 32. Gurvich N, Klein PS. Lithium and valproic acid: parallels and contrasts in diverse signaling contexts. Pharmacol Ther. 2002;96:4566. 33. Gutierrez MA, Stimmel GL, Aiso JY. Venlafaxine: a 2003 update. Clin Ther. 2003;25:21382154. 34. Hajos M, Fleishaker JC, Filipiak-Reisner JK, et al. The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile. CNS Drug Rev. 2004;10:2344. 35. Harwood AJ, Agam G. Search for a common mechanism of mood stabilizers. Biochem Pharmacol. 2003;66:179189. 36. Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev. 2004;45:104114. 37. Healy D, Whitaker C. Antidepressants and suicide: riskbenefit conundrums. J Psychiatry Neurosci. 2003;28:331337. 38. Heim C, Plotsky PM, Nemeroff CB. Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology. 2004;29:641648. 39. Herman E. Lamotrigine: a depression mood stabiliser. Eur Neuropsychopharmacol. 2004;14(suppl 2):S89S93. 40. Joels M, Verkuyl JM, Van Riel E. Hippocampal and hypothalamic function after chronic stress. Ann N Y Acad Sci. 2003;1007:367378. 41. Jonas BS, Brody D, Roper M, Narrow WE. Prevalence of mood disorders in a national sample of young American adults. Soc Psychiatry Psychiatr Epidemiol. 2003;38:618624. 42. Kempermann G, Kronenberg G. Depressed new neuronsadult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biol Psychiatry. 2003;54:499503.

7. 8.


10. 11. 12. 13. 14. 15. 16.

17. 18.

19. 20. 21. 22. 23.

Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome 43. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the national comorbidity survey. Arch Gen Psychiatry. 1994;51:819. 44. Kleindienst N, Greil W. Lithium in the long-term treatment of bipolar disorders. Eur Arch Psychiatry Clin Neurosci. 2003;253:120125. 45. Lawson K. Tricyclic antidepressants and fibromyalgia: what is the mechanism of action? Expert Opin Investig Drugs. 2002;11:14371445. 46. Lesch KP. Gene-environment interaction and the genetics of depression. J Psychiatry Neurosci. 2004;29:174184. 47. Lucki I, OLeary OF. Distinguishing roles for norepinephrine and serotonin in the behavioral effects of antidepressant drugs. J Clin Psychiatry. 2004;65(suppl 4):1124. 48. MacGillivray S, Arroll B, Hatcher S, et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and metaanalysis. BMJ. 2003;326:1014. 49. Macritchie K, Geddes JR, Scott J, et al. Valproate for acute mood episodes in bipolar disorder. Cochrane Database Syst Rev. 2003;CD004052. 50. Malberg JE. Implications of adult hippocampal neurogenesis in antidepressant action. J Psychiatry Neurosci. 2004;29:196205. 51. Malhi GS, Mitchell PB, Salim S. Bipolar depression: management options. CNS Drugs. 2003;17:925. 52. Mattia C, Coluzzi F. Antidepressants in chronic neuropathic pain. Mini Rev Med Chem. 2003;3: 773784. 53. Nierenberg AA, Papakostas GI, Petersen T, et al. Nortriptyline for treatment-resistant depression. J Clin Psychiatry. 2003;64:3539. 54. Nutt DJ. The neuropharmacology of serotonin and noradrenaline in depression. Int Clin Psychopharmacol. 2002;17(suppl 1):S1S12. 55. Page ME. The promises and pitfalls of reboxetine. CNS Drug Rev. 2003;9:327342. 56. Paul IA, Skolnick P. Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci. 2003;1003:250272. 57. Paykel ES. Life events and affective disorders. Acta Psychiatr Scand Suppl. 2003;418:6166. 58. Peretti S, Judge R, Hindmarch I. Safety and tolerability considerations: tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl. 2000;403:1725. 59. Porter RJ, Gallagher P, Watson S, Young AH. Corticosteroid-serotonin interactions in depression: a review of the human evidence. Psychopharmacology (Berl). 2004; 173:117.


60. Reisner L. Antidepressants for chronic neuropathic pain. Curr Pain Headache Rep. 2003;7:2433. 61. Richelson E. Interactions of antidepressants with neurotransmitter transporters and receptors and their clinical relevance. J Clin Psychiatry. 2003;64(suppl 13):512. 62. Roose SP. Compliance: the impact of adverse events and tolerability on the physicians treatment decisions. Eur Neuropsychopharmacol. 2003;13(suppl 3):S85S92. 63. Sachs GS. Unmet clinical needs in bipolar disorder. J Clin Psychopharmacol. 2003;23(suppl 1):S2S8. 64. Sampson SM. Treating depression with selective serotonin reuptake inhibitors: a practical approach. Mayo Clin Proc. 2001;76:739744. 65. Schnitzer TJ, Ferraro A, Hunsche E, Kong SX. A comprehensive review of clinical trials on the efficacy and safety of drugs for the treatment of low back pain. J Pain Symptom Manage. 2004;28:7295. 66. Sheline YI, Mittler BL, Mintun MA. The hippocampus and depression. Eur Psychiatry. 2002;17(suppl 3):300305. 67. Stahl SM, Grady MM. Differences in mechanism of action between current and future antidepressants. J Clin Psychiatry. 2003;64(suppl 13):1317. 68. Tafet GE, Bernardini R. Psychoneuroendocrinological links between chronic stress and depression. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:893903. 69. Thase ME. Effectiveness of antidepressants: comparative remission rates. J Clin Psychiatry. 2003;64(suppl 2):37. 70. Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:85102. 71. Waraich P, Goldner EM, Somers JM, Hsu L. Prevalence and incidence studies of mood disorders: a systematic review of the literature. Can J Psychiatry. 2004;49:124138. 72. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM. 2003;96:369374. 73. Wong ML, Licinio J. From monoamines to genomic targets: a paradigm shift for drug discovery in depression. Nat Rev Drug Discov. 2004;3:136151. 74. Yamada M, Yasuhara H. Clinical pharmacology of MAO inhibitors: safety and future. Neurotoxicology. 2004;25:215221. 75. Yatham LN. Acute and maintenance treatment of bipolar mania: the role of atypical antipsychotics. Bipolar Disord. 2003;5(suppl 2):719. 76. Youdim MB, Weinstock M. Therapeutic applications of selective and non selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation. Neurotoxicology. 2004;25:243250.

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Antipsychotic Drugs
Psychosis is the term used to describe the more severe forms of mental illness. Psychoses are actually a group of mental disorders characterized by marked thought disturbance and an impaired perception of reality. The most common form of psychosis by far is schizophrenia; it is estimated that 1 percent of the world population has the disorder.23,47 Other psychotic disorders include psychotic depression and severe paranoid disorders. In the past, strong, sedativelike drugs were the primary method of treating patients with psychosis. The goal was to pacify these patients so that they were no longer combative and abusive to themselves and others. These drugs were commonly referred to as major tranquilizers and had the obvious disadvantage of sedating a patient so that his or her cognitive and motor skills were compromised. As researchers learned more about the neurologic changes involved in psychosis, drugs were developed to specifically treat disorders rather than simply sedate the patient. These antipsychotic drugs, or neuroleptics, as some clinicians refer to them, represent a major breakthrough in the treatment of schizophrenia and other psychotic disorders. Physical and occupational therapists frequently encounter patients taking antipsychotics. Therapists employed in a psychiatric facility will routinely treat patients taking these medications. Therapists who practice in nonpsychiatric settings may still encounter these patients for various reasons. For instance, a patient on an antipsychotic medication who sustains a fractured hip may be seen at an orthopedic facility. Consequently, knowledge of antipsychotic pharmacology will be useful to all rehabilitation specialists. Because of the prevalence of schizophrenia, this chapter concentrates on the treatment of this psychotic disorder. Also, the pathogenesis and subsequent treatment of other forms of psychosis are similar to those of schizophrenia, and this specific condition will be used as an example of the broader range of psychotic conditions.

The Diagnostic and Statistical Manual of Mental Disorders lists several distinct criteria necessary for a diagnosis of schizophrenia.5 These criteria include a marked disturbance in the thought process, which may include bizarre delusions and auditory hallucinations (i.e., hearing voices). Also, a decreased level of function in work, social relations, and self-care may be present. Other factors include the duration of these and additional symptoms (at least 6 months) and a differential diagnosis from other forms of mental illness (such as affective disorders and organic brain syndrome). The exact cause of schizophrenia has been the subject of extensive research. It appears that genetic factors (i.e., chromosomal abnormalities that cause deviations in brain structure and function) are the primary risk factors in the majority of people with schizophrenia (70% to 80%).15,23 Environmental factors (social stresses, prenatal or childhood brain injury, and so forth) seem to be the underlying cause in the remaining 20% to 30% of people with schizophrenia.23 The precise role of these factors, and the interplay between genetic and environmental factors, continues to be elucidated.28,50, 61 The advent of antipsychotic drugs represents one of the most significant developments in the treatment of schizophrenia and similar disorders. These drugs are believed to be the single most important reason for the abrupt decrease in the number of mental patients admitted to public hospitals during the 1950s and 1960s.22 This observation does not imply that these


SECTION 2 Pharmacology of the Central Nervous System

drugs cure schizophrenia. Schizophrenia and other psychoses are believed to be incurable, and psychotic episodes can recur throughout a patients lifetime. However, these drugs can normalize the patients behavior and thinking during an acute psychotic episode, and maintenance dosages are believed to help prevent the recurrence of psychosis. Consequently, the ability of people with psychosis to take care of themselves and cooperate with others is greatly improved.

Neurotransmitter Changes in Schizophrenia

Schizophrenia appears to be caused by an overactivity of dopamine pathways in certain parts of the brain such as the limbic system.2,23 This idea is based primarily on the fact that most antipsychotics block dopamine receptors, thereby reducing dopaminergic hyperactivity in mesolimbic pathways and other limbic structures (see the next section of this chapter). The increased dopamine influence underlying psychosis could be caused by excessive dopamine synthesis and release by the presynaptic neuron, decreased dopamine breakdown at the synapse, increased postsynaptic dopamine receptor sensitivity, or a combination of these and other factors. Consequently, increased dopamine transmission in areas such as the limbic system seems to be the primary neurochemical change associated with schizophrenia and other psychotic syndromes. However, given the complexity of central neurotransmitter interaction, changes in dopamine activity in the limbic system will almost certainly result in changes in other neurotransmitters in other parts of the brain. Indeed, there is substantial evidence that individuals with psychosis might also have decreased activity in cortical pathways that use glutamate as a neurotransmitter,15,37,41 and it seems likely that other transmitters such as gamma-aminobutyric acid (GABA) and 5hydroxytriptamine (serotonin) may also be affected during the pathogenesis and treatment.16,23 Moreover, the increased dopamine activity in subcortical structures may result in an decreased activity in cortical dopamine activity.2 This imbalance in dopamine activity in different brain regions might explain the different symptoms associated with psychosis. That is, positive symptoms such as agitation and hallucinations might be caused by excess dopamine influence in subcortical regions, whereas negative symptoms such as withdrawn behavior and cognitive

impairment might result from diminished cortical dopamine activity.1 Hence, it appears that the primary neurochemical change in schizophrenia is increased dopamine activity in certain limbic structures, but that this dopamine hyperactivity brings about subsequent changes in neurotransmitter activity in other areas of the brain as well. Resolving all these neurochemical changes might ultimately provide optimal treatment for people with schizophrenia and other forms of psychosis. For now, however, antipsychotic drugs are mainly focused on resolving the increased dopaminergic activity that seems to initiate psychosis. These drugs are discussed in more detail in the next sections of this chapter.

Antipsychotic Mechanism of Action

Antipsychotic drugs used to successfully treat schizophrenia block central dopamine receptors to some extent (Fig. 81).19,23 These drugs share some structural similarity to dopamine, which allows them to bind to the postsynaptic receptor, but they do not activate it. This action effectively blocks the receptor from the effects of the released endogenous neurotransmitter (see Fig. 81). Any increased activity at central dopamine synapses is therefore negated by a postsynaptic receptor blockade. It has become evident, however, that there are several subcategories of dopamine receptors, and these receptor subtypes are identified as D1, D2, D3,
Antipsychotic Drug

Presynaptic terminal

Postsynaptic neuron


FIGURE 81 Effects of antipsychotic drugs on dopamine synapses. Antipsychotics act as postsynaptic receptor antagonists to block the effects of overactive dopamine transmission.

Chapter 8 Antipsychotic Drugs


and so on.18 The clinical effects and side effects of specific antipsychotic medications are therefore related to their ability to affect certain dopamine receptor populations. The receptor that appears to be most important in mediating antipsychotic effects is the D2 receptor subtype.32,51 Most antipsychotic medications therefore have some ability to block the D2 subtype. It is also clear, however, that other dopamine receptor subtypes play a role in the pathogenesis of psychosis, and that certain antipsychotic drugs may produce specific effects because of their affinity for specific receptor subtypes. For example, newer antipsychotics such as clozapine block D4 receptors, and this action may help explain differences in the effects and side effects of these drugs.62 Consequently, antipsychotic drugs all share a basic mechanism of action that involves dopamine receptor blockade. It is apparent, however, that they are not all equal in their ability to affect specific subtypes of dopamine receptors, and that their effectiveness and side effects are related to their affinity and preference for certain receptors. As indicated earlier, other neurotransmitters may also be involved in the pathogenesis of psychosis, and differences in specific antipsychotic medications may be related to their ability to directly or indirectly affect these other transmitters as well as block dopamine influence. Future studies will continue to clarify how current antipsychotics exert their beneficial effects and how new agents can be developed to be more selective in their effects on dopamine and other neurotransmitter pathways.

creased incidence of extrapyramidal (motor) side effects. This increased risk may be due to the traditional agents tendencies to bind to several types of CNS dopamine receptors, including the receptors that influence motor function. This fact seems especially true for high-potency traditional agents such as haloperidol (Haldol) and fluphenazine (Prolixin). These agents have a strong affinity for CNS dopamine receptors and can exert beneficial effects when used in low dosages (see Table 81). Other traditional agents such as chlorpromazine (Thorazine) and thioridazine (Mellaril) have lower potency and must be used in high dosages to exert an antipsychotic effect. These low-potency agents tend to cause fewer extrapyramidal (motor) side effects but are associated with an increased incidence of other problems, such as sedative and anticholinergic side effects (e.g., dry mouth, constipation, urinary retention). These side effects and their possible long-term implications are discussed further in this chapter. Traditional agents are also somewhat less predictable, and there tends to be more patient-to-patient variability in the beneficial (antipsychotic) effects of these medications.18 Newer atypical drugs may be somewhat safer and more predictable, and these agents are described next.

Atypical Antipsychotics
Several newer antipsychotic medications have been developed that seem different or atypical, compared with their predecessors. These agents include clozapine (Clozaril), risperidone (Risperdal), and several others listed in Tables 81 and 82. Although there is some debate about what exactly defines these drugs as atypical, the most distinguishing feature is that they have a much better side-effect profile, including a decreased risk of producing extrapyramidal (motor) side effects.17,45,57 These newer, atypical agents seem to affect certain dopamine receptor subtypes differently than the older, more conventional drugs. In particular, the atypicals do not block the D2 receptors in the basal ganglia as strongly as conventional antipsychotics, hence their reduced risk of motor side effects.52 There is also evidence that these drugs might have beneficial effects on other neurotransmitters, including glutamate, serotonin, and acetylcholine.6,23,52 These additional effects might add to their antipsychotic benefits by improving cognition and reducing the incidence of other problems such as social withdrawal.52

Antipsychotic Medications
Antipsychotic medications are listed in Tables 81 and 82. These agents comprise a somewhat diverse group in terms of their chemical background and potency that is, the dosage range typically needed to achieve antipsychotic effects. As indicated earlier, these agents all block dopamine receptors to some extent, despite their chemical diversity. In addition to their chemical differences, antipsychotics can be classified as either traditional agents or newer atypical antipsychotics according to their efficacy and side effects. Differences between these two classes are described here.

Traditional Antipsychotics
Traditional antipsychotics are associated with more side effects than newer counterparts, including an in-


SECTION 2 Pharmacology of the Central Nervous System

Table 81
Generic Name Aripiprazole*** Chlorpromazine Clozapine*** Fluphenazine Haloperidol Loxapine Molindone Mesoridazine Olanzapine*** Perphenazine Prochlorperazine Quetiapine*** Risperidone*** Thioridazine Thiothixene Trifluoperazine Triflupromazine Ziprasidone***


Trade Name Abilify Thorazine Clozaril Permitil, Prolixin Haldol Loxitane Moban Serentil Zyprexa Trilafon, Triavil Comazol, Compazine Seroquel Risperdal Mellaril Navane Stelazine Vesprin Geodon Usual Dosage Range (mg/d)* 1030 100800 50600 220 220 1080 10100 50400 1020 1064 15150 250600 26 100800 440 540 6150 40160 Maximum recommended dosage (mg/d)** 30 1000 900 40 100 250 225 500 20 64 150 800 16 800 60 80 150 200

*Dosage range represents usual adult oral dose. Lower dosages may be indicated for older or debilitated patients. **Maximum recommended dosage represents the upper limit that can be administered each day to control severe psychotic symptoms, usually in hospitalized patients. ***Atypical antipsychotics. See text for details.

Regarding efficacy, the newer atypical agents seem to be at least as effective as the conventional drugs, but the atypical drugs can reduce the incidence of relapse compared to conventional agents.23,46 Given the therapeutic benefits and reduced risk of side effects, these atypical drugs are usually considered first when treating psychosis.23 If these atypical drugs are not effective, the more conventional or traditional agents are administered.23,45

Antipsychotics are usually administered orally. During the acute stage of a psychotic episode, the daily dosage is often divided into three or four equal amounts. Maintenance doses are usually lower and can often be administered once each day. Under certain conditions, antipsychotics can be given intramuscularly.

Chapter 8 Antipsychotic Drugs


Table 82
Drug Chlorpromazine Fluphenazine Haloperidol Loxapine Mesoridazine Molindone Perphenazine Prochlorperazine Thioridazine Thiothixene Trifluoperazine Triflupromazine


Sedation Extrapyramidal Effects Traditional antipsychotics Anticholinergic Effects

Atypical antipsychotics Aripiprazole Clozapine Olanzapine Quetiapine Risperidone Ziprasidone


of side effects are classified as follows: a very low incidence, moderate incidence, and a high incidence.

a low incidence,

During acute episodes, intramuscular injections tend to reach the bloodstream faster than an orally administered drug and may be used if the patient is especially agitated. Conversely, certain forms of intramuscular antipsychotics that enter the bloodstream slowly have been developed. This method of depot administration may prove helpful if the patient has poor selfadherence to drug therapy and neglects to take his or

her medication regularly.10,34 For example, depot preparations of conventional antipsychotics such as fluphenazine decanoate and haloperidol decanoate, can be injected every 2 to 4 weeks, respectively, and serve as a method of slow, continual release during the maintenance phase of psychosis.4 More recently, an injectable form of risperidone, an atypical antipsychotic, has been developed, and this product might provide beneficial long-term effects with fewer side effects.10,26


SECTION 2 Pharmacology of the Central Nervous System

Metabolism of antipsychotics is through two mechanisms: conjugation with glucuronic acid and oxidation by hepatic microsomal enzymes. Both mechanisms of metabolism and subsequent inactivation take place in the liver. Some degree of enzyme induction may occur because of prolonged use of antipsychotics, which may be responsible for increasing the rate of metabolism of these drugs.

Other Uses of Antipsychotics

Occasionally, antipsychotics are prescribed for conditions other than classic psychosis. As discussed in Chapter 7, an antipsychotic can be used alone or combined with lithium during an acute manic phase of bipolar disorder.9,43 These drugs are also effective in decreasing nausea and vomiting occurring when dopamine agonists and precursors are administered to treat Parkinson disease. The antiemetic effect of antipsychotics is probably caused by their ability to block dopamine receptors located on the brainstem that cause vomiting when stimulated by the exogenous dopamine. Antipsychotics are often used in Alzheimer disease and other cases of dementia to help control aggression and agitation.7,38,58 There is concern, however, that these agents should be used carefully in patients with Alzheimer disease, and that these drugs should not be overused just to sedate these patients. Likewise, side effects should be minimized by considering one of the newer atypical agents, and by using the lowest effective dose.33,38,40 Still, additional research is needed to determine how these drugs can be used most effectively to improve quality of life in people with various forms of dementia.27,30,56

Problems and Adverse Effects

Extrapyramidal Symptoms
One of the more serious problems occurring from the use of antipsychotics is the production of abnormal movement patterns.36,44 Many of these aberrant movements are similar to those seen in patients with lesions of the extrapyramidal system and are often referred to as extrapyramidal side effects. The basic reason that these motor problems occur is because dopamine is an important neurotransmitter in motor pathways, especially in the integration of motor function that takes place in the basal ganglia. Because antipsychotic drugs block CNS dopamine receptors, it makes sense that

motor side effects are a potential complication. The unintentional antagonism of dopamine receptors in areas of motor integration (as opposed to the beneficial blockade of behaviorally related receptors) results in a neurotransmitter imbalance that creates several distinct types of movement problems. Thus, most antipsychotics are associated with some type of motor side effect because these drugs are relatively nonselective in their ability to block CNS dopamine receptors. As noted earlier, the newer (atypical) agents such as clozapine and resperidone are not associated with as high an incidence of extrapyramidal side effects. Several hypotheses exist to explain the lower incidence, including the idea that the atypical antipsychotics block serotonin receptors more than the dopamine type 2 (D2) receptors associated with motor side effects.13 Alternatively, it has been proposed that atypical agents block dopamine receptors long enough to cause a therapeutic effect, but not long enough to cause receptor supersensitivity and other changes that result in motor side effects.13 The exact reasons for their lower incidence of extrapyramidal side effects, however, is not known. At present, however, extrapyramidal side effects continue to be one of the major drawbacks of antipsychotic medications. The primary types of extrapyramidal side effects, the manifestations of each type, and the relative time of their onset are shown in Figure 82. Some factors involved in patient susceptibility and possible treatment of these side effects are discussed here. Tardive Dyskinesia. The disorder of tardive dyskinesia is characterized by a number of involuntary and fragmented movements.21 In particular, rhythmic movements of the mouth, tongue, and jaw are present, and the patient often produces involuntary sucking and smacking noises. Because this condition often involves the tongue and orofacial musculature, serious swallowing disorders (dysphagia) may also occur.55 Other symptoms include choreoathetoid movements of the extremities and dystonias of the neck and trunk. As indicated in Table 82, certain antipsychotics, such as the traditional high-potency drugs, are associated with a greater incidence of tardive dyskinesia. Other risk factors include advanced patient age, affective mood disorders, diabetes mellitus, history of alcohol abuse, and continual use of the drug for 6 months or longer.18,29,49 On the other hand, use of newer, atypical antipsychotics is associated with a much lower risk of tardive dyskinesia, even in high-risk patients.20,31 Still, tardive dyskinesia is relatively common, with an estimated prevalence of 24% of people with chronic psychosis.36

Chapter 8 Antipsychotic Drugs


Acute Dystonic Reactions 1. Torticollis 2. Facial Grimacing 3. Abnormal Eye Movements 4. Involuntary Muscle Movements

Akathisia 1. Restlessness 2. Difficulty in Sitting Still 3. Strong Urge to Move About

Tardive Dyskinesia 1. Protrusion of Tongue 2. Puffing of Cheeks 3. Chewing Movements 4. Involuntary Movements of Extremities 5. Involuntary Movement of Trunk

Pseudo-Parkinsonism 1. Motor Retardation 2. Mask-Like Facies 3. Tremor 4. Pill-Rolling 5. Rigidity 6. Salivation 7. Shuffling Gait





FIGURE 82 Extrapyramidal side effects and their relative onset after beginning antipsychotic drug therapy.

Tardive dyskinesia induced by antipsychotic drugs may be caused by disuse supersensitivity of the dopamine receptor.12,36 Although the presynaptic neurons are still intact, drug blockade of the postsynaptic receptor induces the postsynaptic neuron to respond by up-regulating the number or sensitivity of the receptors. This increase in receptor sensitivity causes a functional increase in dopaminergic influence, leading to a neurotransmitter imbalance between dopamine and other central neurotransmitters such as acetylcholine and GABA. In addition, changes in the structure of striatonigral neurons and other brain structures appear to accompany the functional changes in neurotransmitter sensitivity.12,36 These functional and structural changes result in the symptoms of tardive dyskinesia. Tardive dyskinesia is the most feared side effect of antipsychotic drugs.24 In some patients, the symptoms will disappear if the drug is stopped or if the dosage is decreased, but this can take from several weeks to several years to occur. In other individuals, drug-induced tardive dyskinesia appears irreversible.24 To prevent the occurrence of tardive dyskinesia, the lowest effective dose of the antipsychotic should be used, especially during the maintenance phase of drug therapy.18 Also, patients taking these drugs for three months or more should undergo periodic reevaluation for any

symptoms of tardive dyskinesia.18 The motor symptoms of tardive dyskinesia can be dealt with by lowering the drug dosage or by substituting an antipsychotic that produces fewer extrapyramidal side effects (see Table 82). Early intervention is generally believed to be the most effective way of preventing the permanent changes associated with antipsychotic-induced tardive dyskinesia.21 Other drugs have been used to try to alleviate the symptoms of drug-induced tardive dyskinesia.53,54 Agents such as anticholinergic drugs (e.g., atropinelike drugs), GABA-enhancing drugs (e.g., benzodiazepines), and calcium channel blockers have been used to attempt to rectify the transmitter imbalance or the cellular changes created by the increased dopamine sensitivity. Reserpine has also been used in some patients because of its ability to deplete presynaptic stores of dopamine, thus limiting the influence of this neurotransmitter. However, these additional agents tend to be only marginally successful in reducing the dyskinesia symptoms, and their use tends to add complexity to the drug management of patients with psychoses. Thus, the best course of action continues to be judicious administration of these drugs, using the lowest effective dose, and early recognition and intervention if extrapyramidal symptoms appear.18

(From Feigenbaum JC and Schneider F. Antipsychotic medications. In: Mathewson MK, ed. Pharmacotherapeutics: A Nursing Approach. Philadelphia: FA Davis; 1986: 404, with permission.)


SECTION 2 Pharmacology of the Central Nervous System

Pseudoparkinsonism. The motor symptoms seen in Parkinson disease (see Chapter 10) are caused by a deficiency in dopamine transmission in the basal ganglia. Because antipsychotic drugs block dopamine receptors, some patients may understandably experience symptoms similar to those seen in Parkinson disease. These symptoms include resting tremor, bradykinesia, and rigidity. Elderly patients are more susceptible to these drug-induced parkinsonian-like symptoms, probably because dopamine content (and therefore dopaminergic influence) tends to be lower in older individuals.22 The outcome of antipsychoticinduced parkinsonism is usually favorable, and these symptoms normally disappear when the dosage is adjusted or the drug is withdrawn. Drugs used as adjuncts in treating Parkinson disease (e.g., amantadine, benztropine mesylate) may also be administered to deal with parkinsonianlike side effects.11 However, primary antiparkinsonian drugs such as levodopa and dopamine agonists are not typically used to treat these side effects because they tend to exacerbate the psychotic symptoms. Akathisia. Patients taking antipsychotics may experience sensations of motor restlessness and may complain of an inability to sit or lie still. This condition is known as akathisia.25,35 Patients may also appear agitated, may pace the floor, and may have problems with insomnia. Akathisia can usually be dealt with by altering the dosage or type of medication. If this is unsuccessful, beta-2 adrenergic receptor blockers (propranolol) may help decrease the restlessness associated with akathisia by a mechanism involving central adrenergic receptors.25 Anticholinergic drugs may also be used to treat akathisia, but it is not clear if these drugs actually reduce symptoms associated with akathisia.42 Dyskinesia and Dystonias. Patients may exhibit a broad range of movements in the arms, legs, neck, and face including torticollis, oculogyric crisis, and opisthotonos.8 These movements are involuntary and uncoordinated, and may begin fairly soon after initiating antipsychotic therapy (i.e., even after a single dose).8 If they persist during therapy, other drugs such as antiparkinsonian adjuncts or benzodiazepines (e.g., diazepam) may be used to try to combat the aberrant motor symptoms. Neuroleptic Malignant Syndrome. Patients taking relatively high doses of the more potent antipsychotics may experience a serious disorder known as neuroleptic malignant syndrome (NMS).48 Symptoms of NMS

include catatonia, stupor, rigidity, tremors, and fever.14 These symptoms are rather severe, and can lead to death if left untreated.48 Treatment typically consists of stopping the antipsychotic drug and providing supportive care. The exact causes of NMS are unclear, but the risk of developing this syndrome is increased in patients who are mentally retarded, who are agitated, or when traditional antipsychotics are administered at high doses or via intramuscular injection.60

Nonmotor Effects
Antipsychotics have varying degrees of sedative properties. Contrary to previous beliefs, sedative properties do not enhance the antipsychotic efficacy of these drugs. Consequently, sedative side effects offer no benefit and can be detrimental in withdrawn psychotic patients.

Anticholinergic Effects
Some antipsychotics also produce significant anticholinergic effects, manifested by a variety of symptoms such as blurred vision, dry mouth, constipation, and urinary retention. Fortunately, these problems are usually self-limiting as many patients become tolerant to the anticholinergic side effects while remaining responsive to the antipsychotic properties.

Other Side Effects

Orthostatic hypotension is a frequent problem during the initial stages of antipsychotic therapy. This problem usually disappears after a few days. Certain antipsychotic drugs such as chlorpromazine are associated with photosensitivity, and care should be taken when exposing these patients to ultraviolet irradiation. The newer, atypical drugs can produce metabolic side effects that result in substantial weight gain, increased plasma lipids, and diabetes mellitus.3,39 Thus, these newer drugs pose less risk of motor symptoms, but can cause side effects that ultimately produce serious cardiovascular and endocrine problems.3,59 Finally, abrupt withdrawal of antipsychotic drugs after prolonged use often results in nausea and vomiting, so it is advisable to decrease dosage gradually rather than to suddenly stop administration.

Chapter 8 Antipsychotic Drugs


Special Concerns in Rehabilitation Patients

Antipsychotic drugs have been a great benefit to patients seen in various rehabilitation facilities. Regardless of the reason these individuals are referred to physical therapy and occupational therapy, the improved behavior and reality perception usually provided by drug therapy will surely enhance the patients cooperation during rehabilitation. Because these drugs tend to normalize patient behavior, the withdrawn patient often becomes more active and amiable, while the agitated patient becomes calmer and more relaxed. Also, remission of some confusion and impaired thinking will enable the patient to follow instructions more easily. Patients with paranoid symptoms may have fewer delusions of persecution and will feel less threatened by the entire therapy environment. The benefits of antipsychotic drugs must be weighed against their side effect risks. The less serious side effects such as sedation and some of the anticholinergic effects (blurred vision, dry mouth, constipation) can be bothersome during the treatment session. Orthostatic hypotension should be guarded against, especially during the first few days after drug therapy is initiated. However, the major problems have to do with the antipsychotic drugs extrapyramidal motor effects. Therapists treating patients on antipsychotic medications should remain alert for early signs of motor involvement. Chances are good that the therapist may be the first person to notice a change in posture, balance, or involuntary movements. Even subtle problems in motor function should be brought to the attention of the medical staff immediately. This early intervention may diminish the risk of long-term or even permanent motor dysfunction.

Antipsychotic Drugs
Brief History. R.F., a 63-year-old woman, has been receiving treatment for schizophrenia intermittently for many years. She was last hospitalized for an acute episode 7 months ago and has since been on a maintenance dosage of haloperidol (Haldol), 25 mg/d. She is also being seen as an outpatient for treatment of rheumatoid arthritis in both hands. Her current treatment consists of gentle heat and active range-of-motion exercises, three times each week. She is being considered for possible metacarpophalangeal joint replacement. Problem/Influence of Medication. During the course of physical therapy, the therapist noticed the onset and slow, progressive increase in writhing gestures of both upper extremities. Extraneous movements of her mouth and face were also observed, including chewinglike jaw movements and tongue protrusion. Decision/Solution. These initial extrapyramidal symptoms suggested the onset of tardive dyskinesia. The therapist notified the patients physician, and drug therapy was progressively shifted from haloperidol to the atypical agent clozapine (Clozaril), 450 mg/d. The extrapyramidal symptoms gradually diminished over the next 8 weeks and ultimately disappeared.

Antipsychotic drugs represent one of the major advances in the management of mental illness. Drugs are currently available that diminish the symptoms of psychosis and improve a patients ability to cooperate

with others and to administer self-care. Despite their chemical diversity, antipsychotics all seem to exert beneficial effects by blocking central dopamine receptors. Therefore, psychoses such as schizophrenia may be caused by an overactivity of CNS dopaminergic pathways.


SECTION 2 Pharmacology of the Central Nervous System

Because of the rather nonspecific blockade of dopaminergic receptors, antipsychotics are associated with several adverse side effects. The most serious of these are abnormal movement patterns that resemble tardive dyskinesia, Parkinson disease, and other lesions associated with the extrapyramidal system. In some cases, these aberrant motor activi-

ties may become irreversible and persist even after drug therapy is terminated. Rehabilitation specialists may play a critical role in recognizing the early onset of these motor abnormalities. When identified early, potentially serious motor problems can be dealt with by altering the dosage or type of antipsychotic agent.

1. Abi-Dargham A. Do we still believe in the dopamine hypothesis? New data bring new evidence. Int J Neuropsychopharmacol. 2004;7(suppl 1): S1S5. 2. Abi-Dargham A, Moore H. Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. Neuroscientist. 2003;9:404416. 3. Abidi S, Bhaskara SM. From chlorpromazine to clozapineantipsychotic adverse effects and the clinicians dilemma. Can J Psychiatry. 2003;48:749755. 4. Altamura AC, Sassella F, Santini A, et al. Intramuscular preparations of antipsychotics: uses and relevance in clinical practice. Drugs. 2003;63:493512. 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Revised 4th ed. Washington, DC: American Psychiatric Association; 1994. 6. Ananth J, Parameswaran S, Hara B. Drug therapy in schizophrenia. Curr Pharm Des. 2004;10:22052217. 7. Ballard CG, Margallo-Lana ML. The relationship between antipsychotic treatment and quality of life for patients with dementia living in residential and nursing home care facilities. J Clin Psychiatry. 2004;65(suppl 11):2328. 8. Ballerini M, Bellini S, Niccolai C, et al. Neurolepticinduced dystonia: incidence and risk factors. Eur Psychiatry. 2002;17:366368. 9. Belmaker RH. Bipolar disorder. N Engl J Med. 2004;351:476486. 10. Bhanji NH, Chouinard G, Margolese HC. A review of compliance, depot intramuscular antipsychotics and the new long-acting injectable atypical antipsychotic risperidone in schizophrenia. Eur Neuropsychopharmacol. 2004;14:8792. 11. Burgyone K, Aduri K, Ananth J, Parameswaran S. The use of antiparkinsonian agents in the management of drug-induced extrapyramidal symptoms. Curr Pharm Des. 2004;10:22392248. 12. Casey DE. Tardive dyskinesia: pathophysiology and animal models. J Clin Psychiatry. 2000;61(suppl 4):59. 13. Casey DE. Pathophysiology of antipsychotic druginduced movement disorders. J Clin Psychiatry. 2004;65(suppl 9):2528. 14. Chandran GJ, Mikler JR, Keegan DL. Neuroleptic malignant syndrome: case report and discussion. CMAJ. 2003;169:439442. 15. Collier DA, Li T. The genetics of schizophrenia: glutamate not dopamine? Eur J Pharmacol. 2003;480: 177184.

16. Conley RR, Kelly DL. Current status of antipsychotic treatment. Curr Drug Targets CNS Neurol Disord. 2002;1:123128. 17. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161:414425. 18. Crismon ML, Dorson PG. Schizophrenia. In: DiPiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill; 2002. 19. Dean B, Scarr E. Antipsychotic drugs: evolving mechanisms of action with improved therapeutic benefits. Curr Drug Targets CNS Neurol Disord. 2004;3:217225. 20. Dolder CR, Jeste DV. Incidence of tardive dyskinesia with typical versus atypical antipsychotics in very high risk patients. Biol Psychiatry. 2003;53:11421145. 21. Fernandez HH, Friedman JH. Classification and treatment of tardive syndromes. Neurologist. 2003;9:1627. 22. Finkel SI. Psychotherapeutic agents in older adults. Antipsychotics: old and new. Clin Geriatr Med. 1998; 14:87100. 23. Freedman R. Schizophrenia. N Engl J Med. 2003;349: 17381749. 24. Friedman JH. Historical perspective on movement disorders. J Clin Psychiatry. 2004;65(suppl 9):38. 25. Gogtay N, Sporn A, Alfaro CL, et al. Clozapineinduced akathisia in children with schizophrenia. J Child Adolesc Psychopharmacol. 2002;12:347349. 26. Harrison TS, Goa KL. Long-acting risperidone: a review of its use in schizophrenia. CNS Drugs. 2004;18:113132. 27. Hoeh N, Gyulai L, Weintraub D, Streim J. Pharmacologic management of psychosis in the elderly: a critical review. J Geriatr Psychiatry Neurol. 2003;16: 213218. 28. Howes OD, McDonald C, Cannon M, et al. Pathways to schizophrenia: the impact of environmental factors. Int J Neuropsychopharmacol. 2004;(suppl 1):S7S13. 29. Jeste DV. Tardive dyskinesia in older patients. J Clin Psychiatry. 2000;61(suppl 4):2732. 30. Jeste DV, Dolder CR. Treatment of non-schizophrenic disorders: focus on atypical antipsychotics. J Psychiatr Res. 2004;38:73103. 31. Kane JM. Tardive dyskinesia rates with atypical antipsychotics in adults: prevalence and incidence. J Clin Psychiatry. 2004;65(suppl 9):1620. 32. Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27: 10811090.

Chapter 8 Antipsychotic Drugs 33. Kasckow JW, Mulchahey JJ, Mohamed S. The use of novel antipsychotics in the older patient with neurodegenerative disorders in the long-term care setting. J Am Med Dir Assoc. 2004;5:242248. 34. Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients can do better. J Clin Psychiatry. 2003;64:13081315. 35. Kim JH, Byun HJ. Prevalence and characteristics of subjective akathisia, objective akathisia, and mixed akathisia in chronic schizophrenic subjects. Clin Neuropharmacol. 2003;26:312316. 36. Kulkarni SK, Naidu PS. Pathophysiology and drug therapy of tardive dyskinesia: current concepts and future perspectives. Drugs Today. 2003;39:1949. 37. Laruelle M, Kegeles LS, Abi-Dargham A. Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. Ann N Y Acad Sci. 2003;1003: 138158. 38. Lawlor BA. Behavioral and psychological symptoms in dementia: the role of atypical antipsychotics. J Clin Psychiatry. 2004;65(suppl 11):510. 39. Lebovitz HE. Metabolic consequences of atypical antipsychotic drugs. Psychiatr Q. 2003;74:277290. 40. Lee PE, Gill SS, Freedman M, et al. Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review. BMJ. 2004;329:75. 41. Leriche L, Diaz J, Sokoloff P. Dopamine and glutamate dysfunctions in schizophrenia: role of the dopamine D3 receptor. Neurotox Res. 2004; 6:6371. 42. Lima AR, Weiser KV, Bacaltchuk J, Barnes TR. Anticholinergics for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 2004;CD003727. 43. Masan PS. Atypical antipsychotics in the treatment of affective symptoms: a review. Ann Clin Psychiatry. 2004;16:313. 44. Masand PS. Side effects of antipsychotics in the elderly. J Clin Psychiatry. 2000;61(suppl 8):4349; discussion 5051. 45. Meltzer HY. Whats atypical about atypical antipsychotic drugs? Curr Opin Pharmacol. 2004;4:5357. 46. Mortimer AM. Novel antipsychotics in schizophrenia. Expert Opin Investig Drugs. 2004;13:315329. 47. Mueser KT, McGurk SR. Schizophrenia. Lancet. 2004;363:20632072.


48. Nicholson D, Chiu W. Neuroleptic malignant syndrome. Geriatrics. 2004;59:36, 3840. 49. Oosthuizen PP, Emsley RA, Maritz JS, et al. Incidence of tardive dyskinesia in first-episode psychosis patients treated with low-dose haloperidol. J Clin Psychiatry. 2003;64:10751080. 50. Palomo T, Archer T, Kostrzewa RM, Beninger RJ. Gene-environment interplay in schizopsychotic disorders. Neurotox Res. 2004;6:19. 51. Remington G. Understanding antipsychotic atypicality: a clinical and pharmacological moving target. J Psychiatry Neurosci. 2003;28:275284. 52. Serretti A, De Ronchi D, Lorenzi C, Berardi D. New antipsychotics and schizophrenia: a review on efficacy and side effects. Curr Med Chem. 2004; 11:343358. 53. Soares-Weiser KV, Joy C. Miscellaneous treatments for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2003;CD000208. 54. Soares-Weiser K, Rathbone J. Calcium channel blockers for neuroleptic induced tardive dyskinesia. Cochrane Database Syst Rev. 2004;CD000206. 55. Stewart JT. Dysphagia associated with risperidone therapy. Dysphagia. 2003;18:274275. 56. Sultzer DL. Psychosis and antipsychotic medications in Alzheimers disease: clinical management and research perspectives. Dement Geriatr Cogn Disord. 2004;17:7890. 57. Sussman N. Choosing an atypical antipsychotic. Int Clin Psychopharmacol. 2002;17(suppl 3):S29S33. 58. Tariot PN, Profenno LA, Ismail MS. Efficacy of atypical antipsychotics in elderly patients with dementia. J Clin Psychiatry. 2004;65(suppl 11): 1115. 59. Trenton A, Currier G, Zwemer F. Fatalities associated with therapeutic use and overdose of atypical antipsychotics. CNS Drugs. 2003;17:307324. 60. Viejo LF, Morales V, Punal P, et al. Risk factors in neuroleptic malignant syndrome. A case-control study. Acta Psychiatr Scand. 2003;107:4549. 61. Walker E, Kestler L, Bollini A, Hochman KM. Schizophrenia: etiology and course. Annu Rev Psychol. 2004;55:401430. 62. Wong AH, Van Tol HH. The dopamine D4 receptors and mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:10911099.

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Antiepileptic Drugs
Epilepsy is a chronic neurologic disorder characterized by recurrent seizures.33 Seizures are episodes of sudden, transient disturbances in cerebral excitation that occur when a sufficient number of cerebral neurons begin to fire rapidly and in synchronized bursts.42 Depending on the type of seizure, neuronal activity may remain localized in a specific area of the brain, or it may spread to other areas of the brain. In some seizures, neurons in the motor cortex are activated, leading to skeletal muscle contraction via descending neuronal pathways. These involuntary, paroxysmal skeletal muscle contractions seen during certain seizures are referred to as convulsions. However, convulsions are not associated with all types of epilepsy, and other types of seizures are characterized by a wide variety of sensory or behavioral symptoms. Epilepsy is associated with the presence of a group or focus of cerebral neurons that are hyperexcitable, or irritable. The spontaneous discharge of these irritable neurons initiates the epileptic seizure. The reason for the altered excitability of these focal neurons, and thus the cause of epilepsy, varies depending on the patient.20,42 In some patients, a specific incident such as a stroke, tumor, encephalopathy, head trauma, or other CNS injury probably caused damage to certain neurons, resulting in their altered threshold. In other patients, the reason for seizures may be less distinct or unknown, perhaps relating to a congenital abnormality, birth trauma, or genetic factor. A systemic metabolic disorder such as infection, hypoglycemia, hypoxia, or uremia may precipitate seizure activity. Once the cause of the seizures is identified in this last group of individuals, the epilepsy can be treated by resolving the metabolic disorder. Epilepsy resulting from these combined causes affects approximately 5 to 10 people per 1000 in the general population, making this one of the most common neurologic disorders.30 Although some innovative approaches using surgery, neural stimulation, and dietary control have been reported,8,9,32,45 drug therapy remains the primary method for treating epilepsy. In general, antiepileptic medications are successful in eliminating seizures in 50 percent of the patient population, and can reduce seizure activity substantially in an additional 25 percent of patients with epilepsy.20 Some of the newer antiepileptic medications such as gabapentin (Neurontin) have also been used to treat certain types of pain, including neuropathic pain and migraine headaches.25,37 This chapter, however, will focus on the use of these medications in resolving seizure disorders. Several types of drugs are currently available, and certain compounds work best in specific types of epilepsy. Consequently, the type of epilepsy must be determined by observing the patient and using diagnostic tests such as electroencephalography (EEG).21 The classification system most commonly used in characterizing epilepsy is discussed here.

Classification of Epileptic Seizures

In an attempt to standardize the terminology used in describing various forms of epilepsy, the International League Against Epilepsy10 proposed the classification scheme outlined in Table 91. Seizures are divided into two major categories: partial and generalized. A third category of unclassified seizures is sometimes included to encompass additional seizure types not fitting into the two major groups. Originally devised in the 1980s, this classification system has been revised periodically, and it will undoubtedly continue to be revised as more is learned about the cause and symptoms of specific seizures.29,34


SECTION 2 Pharmacology of the Central Nervous System

Table 91
Seizure Type

Classification Limited (focal) motor or sensory signs (e.g., convulsions confined to one limb, specific sensory hallucinations); consciousness remains intact Consciousness impaired; bizarre behavior; wide variety of other manifestations; specific electroencephalography (EEG) abnormality Symptoms progressively increase until seizure resembles a generalized (tonic-clonic) seizure

I. Partial seizures A. Simple partial seizures

B. Complex partial seizures (needed to differentiate this from absence seizures)

C. Partial becoming generalized

II. Generalized seizures A. Absence (petit mal) seizures Sudden, brief loss of consciousness; motor signs may be absent or may range from rapid eye-blinking to symmetrical jerking movements of entire body Sudden, brief, shocklike contractions of muscles in the face and trunk, or in one or more extremities; contractions may be single or multiple; consciousness may be impaired Rhythmic, synchronized contractions throughout the body; loss of consciousness Generalized sustained muscle contractions throughout body; loss of consciousness Major convulsions of entire body; sustained contraction of all muscles (tonic phase) followed by powerful rhythmic contractions (clonic phase); loss of consciousness Sudden loss of muscle tone in the head and neck, one limb, or throughout the entire body; consciousness may be maintained or lost briefly

B. Myoclonic seizures

C. Clonic seizures D. Tonic seizures E. Tonic-clonic (grand mal) seizures

F. Atonic seizures

III. Unclassified seizures All other seizures that do not fit into one of the aforementioned categories.
Source: Modified from Commission on Classification and Terminology of the International League Against Epilepsy, pp 493495,10 with permission.

In partial seizures only part of the brain (i.e., one cerebral hemisphere) is involved, whereas in generalized seizures the whole brain is involved. Partial seizures that spread throughout the entire brain are referred to as partial becoming generalized or secondarily generalized seizures.

Partial and generalized seizures are subdivided depending on the specific symptoms that occur during the epileptic seizure (see Table 91). As a rule, the outward manifestations of the seizure depend on the area of the brain involved. Simple partial seizures that remain localized within the motor cortex for the right

Chapter 9 Antiepileptic Drugs


hand may cause involuntary, spasm like movements of only the right hand. Other partial seizures produce motor and sensory symptoms, and affect consciousness and memory as well. These usually fall into the category of complex partial seizures. Generalized seizures are subclassified depending on the type and degree of motor involvement, as well as other factors such as EEG recordings. The most well-known and dramatic seizure of the generalized group is the tonic-clonic, or grand mal, seizure. Absence, or petit mal, seizures also fall into the generalized seizure category. Drug therapy for generalized and partial seizures is discussed later in Drugs Used to Treat Epilepsy.

membrane.20,39,42 In some cases, however, the exact way that antiepileptic drugs exert their beneficial effects is obscure or unknown.20 Specific details of each chemical class of drugs are discussed here. Because these drugs tend to have many adverse side effects, only the frequently occurring or more serious problems are listed for each category.

Phenobarbital (various trade names) and other barbiturates such as mephobarbital (Mebaral) are prescribed in virtually all types of adult seizures, but seem to be especially effective in generalized tonic-clonic and simple and complex partial seizures. These agents are considered to be very safe and effective in the treatment of seizures, but their use is often limited because of their strong tendency to produce sedation. Primidone (Mysoline) is another barbituratelike drug that is recommended in several types of epilepsy but is particularly useful in generalized tonic-clonic seizures not responding to other drugs. Mechanism of Action. Barbiturates are known to increase the inhibitory effects of GABA (see Chapter 6), and this effect is probably the primary way that these drugs decrease seizure activity. Barbiturates may also produce some of their antiseizure effects by inhibiting calcium entry into excitatory presynaptic nerve terminals and thereby decreasing the release of excitatory neurotransmitters such as glutamate.20 Adverse Side Effects. Sedation (primary problem), nystagmus, ataxia, folate deficiency, vitamin K deficiency, and skin problems are typical side effects. A paradoxical increase in seizures and an increase in hyperactivity may occur in some children.

Rationale for Drug Treatment

Even in the absence of drug therapy, individual seizures are usually self-limiting. Brain neurons are unable to sustain a high level of synaptic activity for more than a few minutes, and the seizure ends spontaneously. However, the uncontrolled recurrence of seizures is believed to cause further damage to the already injured neurons, and can be potentially harmful to healthy cells.15,36 In particular, seizures can cause structural and functional changes in neuronal pathways, resulting in impaired cerebral activity and increased susceptibility to additional seizures.22,36 Certain types of seizures will also be harmful if the patient loses consciousness or goes into convulsions and injures himself or herself during a fall. Certain types of convulsions are potentially fatal if cardiac irregularities result and the individual goes into cardiac arrest. Even relatively minor seizures may be embarrassing to a person, and social interaction may be compromised if the individual is afraid of having a seizure in public. Consequently, a strong effort is made to find an effective way to control or eliminate the incidence of seizures.

Several members of the benzodiazepine group are effective in treating epilepsy, but most are limited because of problems with sedation and tolerance. Some agents such as diazepam (Valium) and lorazepam (Ativan) are used in the acute treatment of status epilepticus (see Treatment of Status Epilepticus), but only a few are used in the long-term treatment of epilepsy. Clonazepam (Klonopin) is recommended in specific forms of absence seizures (e.g., the Lennox-Gastaut variant) and may also be useful in minor generalized seizures such as akinetic spells and myoclonic jerks. Clorazepate (Tranxene) is another benzodiazepine that is occasionally used as an adjunct in certain partial seizures.

Drugs Used to Treat Epilepsy

Table 92 lists the drugs commonly used to treat epilepsy according to their chemical classes and mechanisms of action. These drugs generally try to inhibit firing of certain cerebral neurons, usually by increasing the inhibitory effects of gamma-aminobutyric acid (GABA), by decreasing the effects of excitatory amino acids (glutamate, aspartate), or by altering the movement of ions (sodium, calcium) across the neuronal


SECTION 2 Pharmacology of the Central Nervous System

Table 92


Possible Mechanism of Action Potentiate inhibitory effects of GABA**; may also decrease excitatory effects of glutamate

Chemical Class Barbiturates Amobarbital (Amytal)* Mephobarbital (Mebaral) Pentobarbital (Nembutal)* Phenobarbital (Solfoton, others) Primidone (Mysoline) Secobarbital (Seconal)* Benzodiazepines Clonazepam (Klonopin) Clorazepate (Tranxene) Diazepam (Valium) Lorazepam (Ativan) Carboxylic acids Valproic acid (Depakene, Depakote, others)

Potentiate inhibitory effects of GABA

Unclear; may hyperpolarize membrane through an effect on potassium channels; higher concentrations increase CNS GABA concentrations Primary effect is to stabilize membrane by blocking sodium channels in repetitive-firing neurons; higher concentrations may also influence concentrations of other neurotransmitters (GABA, norepinephrine, others)

Hydantoins Ethotoin (Peganone) Fosphenytoin (Cerebyx)* Mephenytoin (Mesantoin) Phenytoin (Dilantin) Iminostilbenes Carbamazepine (Tegretol) Oxcarbazepine (Trileptal) Succinimides Ethosuximide (Zarontin) Methsuximide (Celontin)
*Parental use only (IV injection). **GABA gamma-aminobutyric acid.

Similar to hydantoins

Affect calcium channels; appear to inhibit spontaneous firing in thalamic neurons by limiting calcium entry

Mechanism of Action. These drugs are known to potentiate the inhibitory effects of GABA in the brain (see Chapter 6), and their antiepileptic properties are probably exerted through this mechanism. Adverse Side Effects. Sedation, ataxia, and behavioral changes can be observed.

This category includes phenytoin (Dilantin), mephenytoin (Mesantoin), ethotoin (Peganone), and fosphenytoin (Cerebyx). Phenytoin is often the first

drug considered in treating many types of epilepsy, and it is especially effective in treating partial seizures and generalized tonic-clonic seizures. Mephenytoin has similar properties but is somewhat more toxic, and ethotoin has been effective in treating absence seizures. The latter two drugs are usually reserved for use if the patient has not responded to other, less toxic drugs. Finally, fosphenytoin can be administered intravenously in emergency situations to treat continuous, uncontrolled seizures (status epilepticus, a condition addressed later in this chapter).

Chapter 9 Antiepileptic Drugs


Mechanism of Action. Phenytoin stabilizes neural membranes and decreases neuronal excitability by decreasing sodium entry into rapidly firing neurons. This drug basically inhibits the ability of sodium channels to reset from an inactive to active state after the neuron has fired an action potential. By inhibiting the reactivation of sodium channels, phenytoin prolongs the time between action potentials (absolute refractory period) so that neurons must slow their firing rate to a normal level. At higher doses, phenytoin may also decrease neuronal excitability by increasing the effects of GABA and by influencing the movement of potassium and calcium across the nerve membrane, but these effects generally occur at higher drug concentrations than those used therapeutically to control seizures. Less is known about the molecular mechanisms of the other drugs in this category, but they probably work by a similar effect on the sodium channels. Adverse Side Effects. Gastric irritation, confusion, sedation, dizziness, headache, cerebellar signs (nystagmus, ataxia, dysarthria), gingival hyperplasia, increased body and facial hair (hirsutism), and skin disorders are typical adverse effects.

Drugs in this category include ethosuximide (Zarontin), methsuximide (Celontin), and phensuximide (Milontin). All three drugs are primary agents in the treatment of absence (petit mal) seizures, but ethosuximide is the most commonly prescribed. Mechanism of Action. These drugs are known to increase the seizure threshold and limit the spread of electrical activity in the brain, but their exact cellular mechanism is unknown. They may exert their beneficial effects by decreasing calcium influx in certain thalamic neurons. The spontaneous, rhythmic entry of calcium into thalamic neurons may be responsible for initiating partial seizures, and the succinimides prevent their onset by blunting calcium influx. Additional research is needed to elaborate on this theory. Adverse Side Effects. Gastrointestinal distress (nausea, vomiting), headache, dizziness, fatigue, lethargy, movement disorders (dyskinesia, bradykinesia), and skin rashes and itching are common side effects.

Valproic Acid
Valproic acid (Depakene, Depakote, other trade names) is classified as a carboxylic acid, and is used primarily to treat absence seizures or as a secondary agent in generalized tonic-clonic forms of epilepsy. This drug is also used to treat bipolar disorder (manicdepression), especially during the acute manic phase (see Chapter 7). Mechanism of Action. High concentrations of valproic acid are associated with increased levels of GABA in the brain, and this increase in GABAergic inhibition may be responsible for this drugs antiepileptic action. However, lower concentrations are still effective in limiting seizures and do not increase CNS GABA, indicating that some other mechanism must occur. This drug may, for example, increase potassium conductance and efflux from certain neurons, thereby hyperpolarizing the neuron and decreasing its excitability. Valproic acid also exerts some of its effects in a manner similar to phenytoin; that is, it limits sodium entry into rapidly firing neurons. Hence, the exact way in which this drug is effective against partial seizures remains to be determined, and valproic acid may actually work through a combination of several different molecular mechanisms. Adverse Side Effects. Gastrointestinal distress, temporary hair loss, weight gain or loss, and impaired platelet function are documented adverse reactions.

The primary drugs in this category are carbamazepine (Tegretol) and oxcarbazepine (Trileptal). Carbamazepine has been shown to be effective in treating all types of epilepsy except absence seizures, and it is often considered the primary agent for treating partial and tonic-clonic seizures. Carbamazepine is regarded as equivalent to phenytoin in efficacy and side effects, and may be substituted for that drug, depending on patient response. Alternatively, oxcarbazepine can be used alone or with other antiepileptics to treat partial seizures in adults, and it is a treatment adjunct in partial seizures in children between ages 4 to 16. Mechanism of Action. These drugs are believed to exert their primary antiepileptic effects in a manner similar to phenytointhat is, they stabilize the neuronal membrane by slowing the recovery of sodium channels firing too rapidly. Carbamazepine may also inhibit the presynaptic uptake and release of norepinephrine, and this effect may contribute to its antiseizure activity. Adverse Side Effects. Dizziness, drowsiness, ataxia, blurred vision, anemia, water retention (because of abnormal antidiuretic hormone [ADH] release), cardiac arrhythmias, and congestive heart failure can occur with use of these drugs.


SECTION 2 Pharmacology of the Central Nervous System

Newer Second-Generation Agents

The medications described earlier have been on the market for many years and have been used routinely for decreasing seizure activity. Beginning with the introduction of felbamate in 1993, several new or second-generation drugs have also been approved by the FDA and are currently in use (Table 93). In most cases, these newer drugs are not more effective than their predecessors.24 These newer agents, however, generally have favorable pharmacokinetic characteristics (absorption, distribution, metabolism, and so forth) and have relatively mild side effects that allow their use along with the more traditional antiseizure medications.5,16 Hence, these newer drugs are often used as adjuncts or add-on therapy to other drugs.11,13 The combinations often allow adequate seizure control in patients who did not respond to a single traditional antiseizure agent. Likewise, as more is learned about these newer drugs, some are being used alone as the initial treatment, or in certain types of seizures that are resistant to other drugs.11,14,12 Second-generation antiseizure medications currently available are described here. Felbamate (Felbatol). Felbamate is indicated for treatment of partial seizures in adults and children as well as generalized absence seizures (Lennox-Gastaut syndrome) in children. Felbamate appears to bind

to specific receptors in the brain (the N-methyl-Daspartate receptor) and block the effects of excitatory amino acids such as glutamate. Reduced influence of these excitatory amino acids results in decreased seizure activity. As indicated, this drug first appeared on the market in 1993, and represented the first new generation antiseizure agent. It was soon recognized, however, that felbamate may cause severe toxic effects such as aplastic anemia and liver failure.20 Felbamate is therefore not widely prescribed and its use is typically limited to patients with severe epilepsy who fail to respond to other antiseizure drugs. Other common side effects include insomnia, headache, dizziness, and gastrointestinal problems (anorexia, nausea, and vomiting). Gabapentin (Neurontin). Gabapentin is used primarily to treat partial seizures in adults and partial seizures in children that have not responded to other treatments. As the name implies, gabapentin was designed to act as a GABA agonist. However, the exact antiseizure mechanism of this drug is unclear.20 Gabapentin appears to work by increasing GABA release or by acting at a receptor that is different from the GABA receptor.3,17 The primary side effects of this drug are sedation, fatigue, dizziness, and ataxia. Lamotrigine (Lamictal). Lamotrigine is used primarily as an adjunct to other medications in adults with partial seizures, although it has also been used

Table 93
Generic Name Felbamate

Trade Name Felbatol Primary Indication(s) Used alone or as an adjunct in partial seizures in adults; treatment adjunct in partial and generalized seizures associated with LennoxGastaut syndrome in children Treatment adjunct in partial seizures in adults and children over age 3 Use alone or as a treatment adjunct in partial seizures in adults over age 16; treatment adjunct in generalized seizures associated with Lennox-Gastaut syndrome in adults and children over age 2 Treatment adjunct in partial onset seizures in adults Treatment adjunct in partial seizures in adults and children over age 12 Treatment adjunct in partial onset seizures Treatment adjunct in partial seizures in adults

Gabapentin Lamotrigine

Neurontin Lamictal

Levetiracetam Tiagabine Topiramate Zonisamide

Keppra Gabitril Topamax Zonegran

Chapter 9 Antiepileptic Drugs


alone to treat partial and generalized seizures in adults and children. This drug exerts some of its effects by a stabilizing sodium channels in a manner similar to carbamazepine and phenytoin. Lamotrigine may also inhibit the release of excitatory amino acids by inhibiting sodium entry into the presynaptic terminals of neurons firing too rapidly.20 The primary side effects include dizziness, headache, ataxia, vision problems, and skin rash. Levetiracetam (Keppra). Levetiracetam has been successful in treating partial seizures in adults when used in conjunction with traditional antiseizure drugs. This drug does not appear to decrease seizure activity via one of the common antiseizure mechanisms (stabilize sodium channels, increase GABA inhibition, and so forth), and the mechanism of this drug is therefore unknown. Levetiracetam is usually well tolerated, although some patients may experience sedation, dizziness, and generalized weakness. Tiagabine (Gabitril). Tiagabine is used primarily as an adjunct to other drugs in adults with partial seizures that are poorly controlled by traditional drug therapy. This drug inhibits the reuptake of GABA after it is released from presynaptic terminals, thereby inhibiting seizure activity by enabling GABA to remain active in the synaptic cleft for longer periods.2 The primary side effects of this drug are dizziness,

weakness, and a slight tendency for psychiatric disturbances (anxiety, depression). Topiramate (Topamax). Topiramate is used primarily as an adjunct to other medications in adults with partial seizures. This drug appears to limit seizure activity through several complimentary mechanisms including inhibition of sodium channel opening, blockade of excitatory amino acid receptors, and stimulation of GABA receptors.2,41 Primary side effects include sedation, dizziness, fatigue, and ataxia. Zonisamide (Zonegran). Zonisamide is used primarily as an adjunct to other medications in adults with partial seizures. This drug stabilizes sodium channels in a manner similar to carbamazepine and phenytoin, and may also exert some of its antiseizure effects by inhibiting calcium entry into rapidly firing neurons. Zonisamide is fairly well tolerated, although side effects may include sedation, ataxia, loss of appetite, and fatigue.

Selection of a Specific Antiepileptic Agent

It is apparent from the preceding discussion that certain drugs are often preferred when treating certain types of seizures. Table 94 lists some of the more

Table 94
Seizure Type Partial seizures


First-line Drugs Carbamazepine Phenytoin Lamotrigine Valproic acid Oxcarbazepine Alternative Agents Gabapentin Topiramate Levetiracetam Zonisamide Tiagabine Primidone, phenobarbital Felbamate

Generalized seizures Absence Myoclonic Tonic-clonic Valproic acid, ethosuximide Valproic acid, clonazepam Phenytoin, carbamazepine, valproic acid Lamotrigine Lamotrigine, topiramate, felbamate Lamotrigine, topiramate, phenobarbital, primidone, oxcarbazepine

Source: Gidal BE, et al. Epilepsy. In: DiPiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill; 2002:1036.


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common types of seizures and the primary and alternative agents used to treat each seizure type. It is important to note, however, that while Table 94 indicates general guidelines for drug selection, selection of the best agent must be done on a patient-by-patient basis. Some patients will understandably exhibit a better response to agents that are not typically used as the first or second choice for a specific type of seizure. Hence, some trial and error may occur before the best drug is found, and drug selection may need to be altered periodically throughout the patients lifetime to achieve optimal results.31

Thus, a fairly large number of drugs can be used to treat epileptic seizures (see Tables 92 and 93), but certain agents are usually considered first when attempting to treat the most common types. These agents comprise a fairly small group that tend to be used most often; the drugs and their relevant dosing parameters are listed in Table 95. Again, alternative antiseizure drugs can be used if commonly used drugs are ineffective or poorly tolerated. As indicated earlier, one of the newer agents can also be added to traditional drugs if patients do not respond to singledrug therapy.

Table 95
Adult Drug Carbamazepine Ethosuximide Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Phenobarbital Phenytoin Primidone Tiagabine Topiramate Valproic acid Zonisamide


Child Initial Dose (mg) 200 BID 250 qd 6001200 qd 300 qd 25 qd 500 BID 300 qd 3060 qd 200 qd 125250 qd 4 qd 25 qd 250 qd 100 qd Increment** (mg) 200 q wk 250 q 37d 6001200 q 12 wk 300 q 37 d 25 q 2 wk 500 q wk 300 q wk 30 q 12 wk 100 q 57 d 250 q 12 wk 48 q wk 25 q 12 wk 250 q 37 d 100 q 2 wk Maintenance (mg/d) 6001800 750 24003600 12003600 400 20004000 9002400 60120 200300 500750 1632 100400 7503000 200400 Initial Dose (mg/kg/d) 10 qd 15 15 10 0.150.5 20 810 3 4 10 0.1 3 15 4 Maintenance (mg/kg/d) 1035 ( 6 years) 1540 1545 2550 5 40100 3046 36 48 1025 0.4 39 1545 412

Abbreviations: BID twice a day; qd every day. *Dosages reflect monotherapy. Dosages may vary if combining the drug with other antiseizure agents, or other drugs that affect liver enzyme function. **Increments reflect the rate that dosage can typically be increased when trying to find the appropriate therapeutic dose. Source: Ranta A, Fountain NB. Seizures and epilepsy in adolescents and adults. In: Rakel RE, Bope ET, eds. Conns Current Therapy 2005. New York: Elsevier/Saunders; 2005: 1026.

Chapter 9 Antiepileptic Drugs


Single-Drug Therapy Versus Drug Combinations in Epilepsy

In the past, an effort was made to use only one drug (primary agent), with an additional drug (secondary agent) being added only if the epilepsy is especially resistant to management with the primary medication.6 The use of a single drug (monotherapy) offers several advantages, including fewer side effects, a lack of drug interactions, better ability of the patient to adhere to the drug regimen, lower cost, and better seizure control because the patient was able to tolerate a higher dose of a single agent.31 Likewise, management of adverse side effects in single-drug therapy is easier because there is no question about which drug is producing the adverse effect. As indicated earlier, the development of the newer antiseizure medications has advanced the strategy of using two drugs rather than a single agent. Because these newer drugs have relatively predictable pharmacokinetic and side-effect profiles, they can be added to traditional medications without excessive complications and risk to the patient.4,31 Combination therapy is therefore a more common approach to treating seizure disorders than it was in the past.

When given for the long-term control of epilepsy, these drugs are normally administered orally. Daily oral doses are usually divided into three or four equal quantities, and the amount of each dose varies widely depending on the specific drug and the severity of patient seizures. Distribution within the body is fairly extensive, with all antiepileptic drugs eventually reaching the brain to exert their beneficial effects. Drug biotransformation usually occurs via liver microsomal oxidases, and this is the primary method of drug termination.

tic.23,26,44 Problems such as stillbirth, microencephaly, mental retardation, infant seizures, and congenital malformations (cleft palate, cardiac defects, neural tube defects) occur more frequently in children of women with seizure disorders. There is considerable debate as to whether this is a side effect of antiepileptic drug therapy or a sequela of the epilepsy itself. Because there is at least some concern that fetal malformations may be a drug side effect, some mothers may choose to discontinue drug therapy during their pregnancies.44 This action obviously places the mother at risk for uncontrolled seizures, which may be even more harmful to the mother and unborn child. Hence, women taking antiepileptic drugs should discuss the potential risks with their family members and physician, and consider whether they will continue taking their medication(s).38 If an expectant mother continues to take her medication(s), using one drug (monotherapy) at the lowest effective dose will help reduce the risk of harmful effects on the fetus.1,43 In addition, mothers should receive optimal prenatal care (folic acid supplementation, proper amounts of exercise, rest, and so forth) to help ensure the babys health.27,43 After delivery, the baby should be monitored initially for drug-related effects such as withdrawal symptoms, and should be subsequently evaluated for developmental delays that might become apparent later in childhood.27

Treatment of Status Epilepticus

Status epilepticus is a series of seizures occurring without any appreciable period of recovery between individual seizures.19,28 Essentially the patient experiences one long, extended seizure. This may be brought on by a number of factors such as sudden withdrawal from antiepileptic drugs, cerebral infarct, systemic or intracranial infection, or withdrawal from addictive drugs including alcohol.19,28 If untreated, status epilepticus will result in permanent damage or death, especially if the seizures are generalized tonic-clonic in nature.18 Consequently, this event is regarded as a medical emergency that should be resolved as rapidly as possible. Treatment begins with standard emergency procedures such as maintaining an airway, starting an IV line for blood sampling and drug administration, and so on.28 The first drugs administered are usually benzodiazepines: lorazepam (Ativan) or diazepam (Valium)

Special Precautions During Pregnancy

Most women with epilepsy continue to take their antiseizure medications when they become pregnant, and eventually give birth to normal, healthy babies.44 Nonetheless, the incidence of birth defects is increased somewhat in children of mothers with epilepsy compared with children of mothers who are not epilep-


SECTION 2 Pharmacology of the Central Nervous System

given intravenously. This approach is followed by phenytoin, which is also administered intravenously. The phenytoin is given concurrently with or immediately after the benzodiazepine so that seizures are controlled when the relatively short-acting benzodiazepine is metabolized. If seizures continue despite these drugs, phenobarbital is given intravenously. If all other attempts fail, general anesthesia (e.g., halothane) may be used as a last resort. When the status epilepticus is eventually controlled, an attempt is made to begin or reinstitute chronic antiepileptic therapy.

Withdrawal of Antiseizure Medications

Many people with seizure disorders will need to adhere to a regimen of antiseizure medications throughout

their lifetime. There appears, however, to be a certain percentage of patients who can discontinue their medications once their seizures are under control. It is estimated, for example, that as many as 60 to 70 percent of people who have epilepsy can remain seizure-free after their medication is withdrawn.7 Factors associated with successful medication withdrawal include being free of seizures for at least 2 years while on medication(s), having a normal neurologic examination prior to withdrawal, and being young when the seizures started.35,40 Withdrawal of medications must, of course, be done under close medical supervision. Likewise, medications are usually tapered-off over an extended period of time (6 months) rather than being suddenly discontinued.7 Nonetheless, it appears that a large proportion of people with epilepsy may be able to maintain seizure-free status once their seizures are controlled by the appropriate medications.

Special Concerns in Rehabilitation Patients

Rehabilitation specialists must always be cognizant of their patients who have a history of seizures and who are taking antiepileptic drugs. Patients being treated for conditions unrelated to epilepsy (e.g., the outpatient with low back pain) should be identified as potentially at risk for a seizure during the therapy session. This knowledge will better prepare the therapist to recognize and deal with such an episode. This approach emphasizes the need for a thorough medical history of all patients. Also, therapists may help determine the efficacy of antiepileptic drug therapy. The primary goal in any patient taking antiepileptic drugs is maintaining the drug dosage within a therapeutic window. Dosage must be high enough to adequately control seizure activity, but not so high as to invoke serious side effects. By constantly observing and monitoring patient progress, rehabilitation specialists may help determine if this goal is being met. By noting changes in either seizure frequency or side effects, physical therapists, occupational therapists, and other rehabilitation personnel may help the medical staff arrive at an effective dosing regimen. This information can be invaluable in helping achieve optimal patient care with a minimum of adverse side effects. Some of the more frequent side effects may affect physical therapy and other rehabilitation procedures. Headache, dizziness, sedation, and gastric disturbances (nausea, vomiting) may be bothersome during the therapy session. Often, these reactions can be addressed by scheduling therapy at a time of day when these problems are relatively mild. The optimal treatment time will vary from patient to patient, depending on the particular drug, dosing schedule, and age of the patient. Cerebellar side effects such as ataxia also occur frequently and may impair the patients ability to participate in various functional activities. If ataxia persists despite efforts to alter drug dosage or substitute another agent, coordination exercises may be instituted to help resolve this problem. Skin conditions (dermatitis, rashes, etc.) are another frequent problem in long-term antiepileptic therapy. Any therapeutic modalities that might exacerbate these conditions should be discontinued.

Chapter 9 Antiepileptic Drugs


Finally, in some patients, seizures tend to be exacerbated by environmental stimuli such as lights and sound. In such patients, conducting the therapy session in a busy, noisy clinic may be sufficient to precipitate a seizure, especially if the epilepsy is poorly controlled by drug therapy. Also, certain patients may have a history of increased seizure activity at certain times of the day, which may be related to when the antiepileptic drug is administered. Consequently, certain patients may benefit if the therapy session is held in a relatively quiet setting at a time when the chance of a seizure is minimal.

Antiepileptic Drugs
Brief History. F.B. is a 43-year-old man who works in the mail room of a large company. He was diagnosed in childhood as having generalized tonic-clonic epilepsy, and his seizures have been managed successfully with various drugs over the years. Most recently, he has been taking carbamazepine (Tegretol), 800 mg/d (i.e., one 200-mg tablet, QID). One month ago, he began complaining of dizziness and blurred vision, so the dosage was reduced to 600 mg/d (one 200 mg tablet TID). He usually took the medication after meals. Two weeks ago, he injured his back while lifting a large box at work. He was evaluated in physical therapy as having an acute lumbosacral strain. He began to attend physical therapy daily as an outpatient. Treatment included heat, ultrasound, and manual therapy, and the patient was also being instructed in proper body mechanics and lifting technique. F.B. continued to work at his normal job, but he avoided heavy lifting. He would attend therapy on his way home from work, at about 5 PM. Problem/Influence of Medication. F.B. arrived at physical therapy the first afternoon stating that he had had a particularly long day. He was positioned prone on a treatment table, and hot packs were placed over his low back. As the heat was applied, he began to drift off to sleep. Five minutes into the treatment, he had a seizure. Because of a thorough initial evaluation, the therapist was aware of his epileptic condition and protected him from injury during the seizure. The patient regained consciousness and rested quietly until he felt able to go home. No long-term effects were noted from the seizure. Decision/Solution. The seizure may have been precipitated by a number of factors, including the recent decrease in drug dosage and the fact that he was nearing the end of a dosing interval. (He had taken his last dose at lunch and would take his next dose after he went home and had dinner.) The fact that he was tired and fell asleep during the treatment probably played a role. He reported later that when seizures do occur, they tend to be when he is asleep. To prevent the recurrence of seizures, the therapy session was rescheduled to earlier in the day, at 8 AM (his schedule was flexible enough that he could attend therapy before going to work). Also, he took his first dose of the day approximately 1 hour before arriving at physical therapy. No further seizures occurred during the course of rehabilitation, and F.B.s lumbosacral strain was resolved after 2 weeks of physical therapy.

Epilepsy is a chronic condition characterized by recurrent seizures. Causes of this disorder range from a distinct traumatic episode to obscure or unknown origins. Seizures are categorized according to the clinical and electrophysiologic manifestations that occur during the seizure. Fortunately, most individuals with epilepsy (up to 75 percent) can be treated successfully with antiepileptic drugs. Although these drugs do

not cure this disorder, reduction or elimination of seizures will prevent further CNS damage. Currently, a wide variety of drugs are used, with certain agents being the most successful in specific types of epilepsy. As in any area of pharmacotherapeutics, these drugs are not without adverse side effects. Some of these side effects may become a problem in rehabilitation patients, so therapists should be ready to alter the time and type of treatment as needed to accommodate these side effects. Physical therapists and


SECTION 2 Pharmacology of the Central Nervous System

other rehabilitation personnel should also be alert for any behavioral or functional changes in the patient that might indicate a problem in drug therapy. Insufficient drug therapy (as evidenced by

increased seizures) or possible drug toxicity (as evidenced by increased side effects) should be brought to the physicians attention so that these problems can be rectified.

1. Adab N, Tudur SC, Vinten J, et al. Common antiepileptic drugs in pregnancy in women with epilepsy. Cochrane Database Syst Rev. 2004;CD004848. 2. Angehagen M, Ben-Menachem E, Ronnback L, Hansson E. Novel mechanisms of action of three antiepileptic drugs, vigabatrin, tiagabine, and topiramate. Neurochem Res. 2003;28:333340. 3. Ashton H, Young AH. GABA-ergic drugs: exit stage left, enter stage right. J Psychopharmacol. 2003;17: 174178. 4. Baulac M. Rational conversion from antiepileptic polytherapy to monotherapy. Epileptic Disord. 2003;5: 125132. 5. Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol. 2004;3:618621. 6. Ben-Menachem E, Scheepers B, Stodieck S. Epilepsy: from consensus to daily practice. Acta Neurol Scand Suppl. 2003;180:515. 7. Britton JW. Antiepileptic drug withdrawal: literature review. Mayo Clin Proc. 2002;77:13781388. 8. Buchhalter JR, Jarrar RG. Therapeutics in pediatric epilepsy, part 2: epilepsy surgery and vagus nerve stimulation. Mayo Clin Proc. 2003;78:371378. 9. Cohen-Gadol AA, Britton JW, Wetjen NM, et al. Neurostimulation therapy for epilepsy: current modalities and future directions. Mayo Clin Proc. 2003; 78:238248. 10. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 1989;30: 389399. 11. Deckers CL, Knoester PD, de Haan GJ, et al. Selection criteria for the clinical use of the newer antiepileptic drugs. CNS Drugs. 2003;17:405421. 12. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:12521260. 13. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:12611273.

14. Gil-Nagel A. Review of new antiepileptic drugs as initial therapy. Epilepsia. 2003;44(suppl 4):310. 15. Haut SR, Veliskova J, Moshe SL. Susceptibility of immature and adult brains to seizure effects. Lancet Neurol. 2004;3:608617. 16. LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. JAMA. 2004;291:605614. 17. Maneuf YP, Gonzalez MI, Sutton KS, et al. Cellular and molecular action of the putative GABA-mimetic, gabapentin. Cell Mol Life Sci. 2003;60:742750. 18. Manno EM. New management strategies in the treatment of status epilepticus. Mayo Clin Proc. 2003;78: 508518. 19. Marik PE, Varon J. The management of status epilepticus. Chest. 2004;126:582591. 20. McNamara JO. Drugs effective in the therapy of the epilepsies. In: Hardman JG, et al, eds. The Pharmacological Basic of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 21. Mendiratta A. Clinical neurophysiology of epilepsy. Curr Neurol Neurosci Rep. 2003;3:332340. 22. Morimoto K, Fahnestock M, Racine RJ. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol. 2004;73:160. 23. Morrow JI, Craig JJ. Anti-epileptic drugs in pregnancy: current safety and other issues. Expert Opin Pharmacother. 2003;4:445456. 24. Onat F, Ozkara C. Adverse effects of new antiepileptic drugs. Drugs Today (Barc). 2004;40:325342. 25. Pappagallo M. Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine. Clin Ther. 2003;25:25062538. 26. Pennell PB. The importance of monotherapy in pregnancy. Neurology. 2003;60(suppl 4):S31S38. 27. Penovich PE, Eck KE, Economou VV. Recommendations for the care of women with epilepsy. Cleve Clin J Med. 2004;71(suppl 2):S49S57. 28. Phelps SJ, Hovinga CA, Boucher BA. Status epilepticus. In: DiPiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill; 2002. 29. Riviello JJ. Classification of seizures and epilepsy. Curr Neurol Neurosci Rep. 2003;3:325331. 30. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol. 2003;16:165170. 31. Sander JW. The use of antiepileptic drugsprinciples and practice. Epilepsia. 2004;45(suppl 6):2834. 32. Shaefi S, Harkness W. Current status of surgery in the management of epilepsy. Epilepsia. 2003;44(suppl 1): 4347. 33. Shneker BF, Fountain NB. Epilepsy. Dis Mon. 2003; 49:426478.

Chapter 9 Antiepileptic Drugs 34. Sirven JI. Classifying seizures and epilepsy: a synopsis. Semin Neurol. 2002;22:237246. 35. Specchio LM, Beghi E. Should antiepileptic drugs be withdrawn in seizure-free patients? CNS Drugs. 2004; 18:201212. 36. Sperling MR. The consequences of uncontrolled epilepsy. CNS Spectr. 2004;9:98101, 106109. 37. Spina E, Perugi G. Antiepileptic drugs: indications other than epilepsy. Epileptic Disord. 2004; 6: 5775. 38. Tatum WO, 4th, Liporace J, Benbadis SR, Kaplan PW. Updates on the treatment of epilepsy in women. Arch Intern Med. 2004;164:137145. 39. Tidwell A, Swims M. Review of the newer antiepileptic drugs. Am J Manag Care. 2003;9: 253276. 40. Verrotti A, Trotta D, Salladini C, et al. Risk factors for recurrence of epilepsy and withdrawal of antiepileptic


41. 42. 43. 44. 45.

therapy: a practical approach. Ann Med. 2003;35: 207215. Waugh J, Goa KL. Topiramate: as monotherapy in newly diagnosed epilepsy. CNS Drugs. 2003;17: 985992. Webster RA. The epilepsies. In: Webster RA, ed. Neurotransmitters, Drugs and Brain Function. New York: John Wiley and Sons; 2001. Yerby MS. Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation. Epilepsia. 2003;44(suppl 3):3340. Yerby MS, Kaplan P, Tran T. Risks and management of pregnancy in women with epilepsy. Cleve Clin J Med. 2004;71(suppl 2):S25S37. Yudkoff M, Daikhin Y, Nissim I, et al. Ketogenic diet, brain glutamate metabolism and seizure control. Prostaglandins Leukot Essent Fatty Acids. 2004;70: 277285.

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Pharmacological Management of Parkinson Disease

Parkinson disease is a movement disorder characterized by resting tremor, bradykinesia, rigidity, and postural instability.3,29,32 In Parkinson disease, there is a slow, progressive degeneration of certain dopaminesecreting neurons in the basal ganglia.29,59,66 Several theories have been proposed to explain this spontaneous neuronal degeneration, including the possibility that the disease may be caused by a combination of genetic and environmental factors (see Etiology of Parkinson Disease: Potential Role of Toxic Substances).22,83 However, the precise initiating factor in Parkinson disease is still unknown. The clinical syndrome of parkinsonism (i.e., rigidity, bradykinesia) may be caused by other factors such as trauma, infectious agents, antipsychotic drugs, cerebrovascular disease, and various forms of cortical degeneration (including Alzheimer disease).46,48,54,63 However, the most frequent cause of parkinsonism is the spontaneous slow, selective neuronal degeneration characteristic of Parkinson disease itself.59,66 Also, the drug management of parkinsonism caused by these other factors closely resembles the management of Parkinson disease.48 Consequently, this chapter will address the idiopathic onset and pharmacologic treatment of Parkinson disease per se. Parkinson disease usually begins in the fifth or sixth decade, and symptoms progressively worsen over a period of 10 to 20 years. It is estimated that more than 1 percent of the U.S. population older than 60 years is afflicted with Parkinson disease, making it one of the most prevalent neurologic disorders affecting elderly individuals.59 In addition to the symptoms of bradykinesia and rigidity, a patient with advanced Parkinson disease maintains a flexed posture and speaks in a low, soft voice (microphonia). If left untreated, the motor problems associated with this illness eventually lead to total incapacitation. Rehabilitation specialists are often involved in treating patients with this illness due to its prevalence and its associated motor problems. Fortunately, the pharmacologic management of Parkinson disease has evolved to where the symptoms associated with this disorder can be greatly diminished in many patients. The use of levodopa (L-dopa) alone or in combination with other drugs can improve motor function and general mobility well into the advanced stages of this disease. Drugs used in treating Parkinson disease do not cure this condition, and motor function often tends to slowly deteriorate regardless of when drug therapy is initiated.51,57,79 However, by alleviating the motor symptoms (i.e., bradykinesia and rigidity), drug therapy can allow patients with Parkinson disease to continue to lead relatively active lifestyles, thus improving their overall physiologic and psychologic well-being.

Pathophysiology of Parkinson Disease

During the past 40 years, the specific neuronal changes associated with the onset and progression of Parkinson disease have been established. Specific alterations in neurotransmitter balance in the basal ganglia are responsible for the symptoms associated with this disorder.59,66 The basal ganglia are groups of nuclei located in the brain that are involved in the coordination and regulation of motor function. One such nucleus, the substantia nigra, contains the cell bodies of neurons that project to other areas such as the putamen and caudate nucleus (known collectively as the corpus striatum). The neurotransmitter used in this nigrostriatal pathway is dopamine. The primary neural abnormality in Parkinson disease


SECTION 2 Pharmacology of the Central Nervous System

is that dopamine-producing cells in the substantia nigra begin to degenerate, resulting in the eventual loss of dopaminergic input into the corpus striatum.48,59 Consequently, the decrease in striatal dopamine seems to be the initiating factor in the symptom onset associated with Parkinson disease. However, it also appears that the lack of dopamine results in an activity increase in basal ganglia cholinergic pathways.3 Illustrated in Figure 101, there is a balance between dopaminergic and cholinergic influence in the basal ganglia under normal conditions. However, the loss of dopaminergic influence in Parkinson disease appears to allow cholinergic influence to dominate. The relationship between these two neurotransmitters suggests that the role of striatal dopamine may be to modulate acetylcholine release; that is, the lack of

inhibitory dopaminergic influence allows excitatory acetylcholine pathways to run wild. Thus, the symptoms associated with Parkinson disease may be directly caused by increased cholinergic influence occurring secondary to dopamine loss. Current research also suggests that other imbalances involving transmitters such as gamma-aminobutyric acid (GABA), 5-hydroxytryptamine (serotonin), endogenous opioids, and excitatory amino acids (glutamate) may also be present in the basal ganglia subsequent to the loss of dopamine.3,66 In any event, drug therapy focuses on resolving the dopamine-acetylcholine imbalance to restore normal motor function in Parkinson disease.

Etiology of Parkinson Disease: Genetic and Environmental Factors

As stated previously, the exact factors that initiate the loss of striatal dopamine are unknown in most patients with Parkinson disease. However, recent evidence suggests that genetic factors may interact with environmental factors to make certain individuals susceptible to the destruction of dopaminergic neurons in the substantia nigra.22,35,83 Regarding the genetic factors, mutations of several genes have been identified that might play a causative role in Parkinson disease.22,35 These genes are responsible for controlling the production of alpha-synuclein (a small presynaptic protein) and other neuronal proteins.6,14,45 Defects in the genes regulating the production of these proteins appear to lead to the overproduction and abnormal accumulation of proteins in neuronal tissues, especially in people with certain forms of Parkinson disease such as early onset parkinsonism and other familial forms.11,34 As proteins accumulate, they can cause damage to specific cellular components such as the mitochondria and cell membrane.33,42 Indeed, Parkinson disease and several other neurodegenerative disorders are associated with the formation of Lewy bodies, which are clumps of proteins found in the neuronal tissues.48,78 Abnormal protein accumulation therefore seems to play a role in the degenerative changes seen in Parkinson disease. The actual neuronal death, however, may be caused by the formation of harmful byproducts of oxygen metabolism, better known as oxygen free radicals.38,75 A free radical is a chemical species that has an unpaired electron in its outer shell.15 In order to become more stable, the free radical steals an electron from some other cellular component such as a

Dopamine Acetylcholine

Basal Ganglia




Basal Ganglia

FIGURE 101 Schematic representation of the neurotransmitter imbalance in Parkinson disease. Normally, a balance exists between dopamine and acetylcholine in the basal ganglia. In Parkinson disease, decreased dopaminergic influence results in increased acetylcholine influence.

Chapter 10 Pharmacological Management of Parkinson Disease


protein, DNA molecule, or membrane phospholipid. In this process, the free radical damages the cellular component, subsequently damaging the cell. Free radicals, for example, might initiate or accelerate the abnormal accumulation and aggregation of alphasynuclein and other proteins within the neuron.20 Consequently, cells subjected to this free radical-induced damage are said to undergo oxidative stress because loss of electrons (oxidation) of proteins and other cellular components leads to harmful effects on the cell.15,33 Hence, oxygen free radicals might ultimately be responsible for causing the degeneration and death of substantia nigra neurons. Production of these free radicals appears to be increased in people with Parkinson disease, either in response to protein accumulation, or because of a primary defect in mitochondrial function.8,14,21 Regardless of the initiating factor, excess production of free radicals in the basal ganglia could lead to a vicious cycle whereby the free radicals accelerate protein accumulation and damage the mitochondria, which in turn causes more free radical production, and so on.30,38 It therefore appears that neurons in the substantia nigra might ultimately be destroyed because genetic factors lead to neuronal protein accumulation and free radical-induced oxidative stress that causes the degeneration and death of these neurons. As indicated earlier, however, the influence of environmental factors should be considered.49,64 It has been theorized, for example, that environmental toxins (e.g., herbicides, insecticides, fungicides) accelerate the neuronal destruction in people with Parkinson disease.14 Much of this evidence is based on the finding that a compound known as 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) appears to be selectively toxic to these neurons and can invoke parkinsonism in primates.84 The theory that a toxin like MPTP might cause Parkinson disease was formulated in a rather interesting fashion. In 1982, several young adults in their 20s and 30s developed permanent, severe parkinsonism.5 Since the onset of Parkinson disease before age 40 is extremely rare, these individuals aroused a great deal of interest. Upon close investigation, all of these individuals were found to have experimented with synthetic heroin-like drugs. These so-called designer drugs were manufactured by drug dealers in an attempt to create an illicit supply of narcotics for sale to heroin addicts. However, the illicit narcotics contained the toxin MPTP, which was discovered to cause selective destruction of substantia nigra neurons.5

The discovery of toxin-induced parkinsonism in drug addicts led to the idea that idiopathic Parkinson disease may occur when susceptible individuals are exposed to some environmental toxin.14 Exposure to such a toxin through industrial waste or certain herbicides may begin the neuronal changes that ultimately result in Parkinson disease. A specific environmental factor, however, has not been identified yet. Nonetheless, it seems possible that environmental factors might interact with genetic factors to bring about the neuronal destruction associated with Parkinson disease. Environmental toxins, for example, might serve as the trigger for neuronal death in people who have genetic variations that make them vulnerable to these toxins. The exact cause of Parkinson disease remains unknown, however, and future research will hopefully clarify the link between genetic factors, environmental factors, and the mechanism of cell death in the substantia nigra. The idea that toxins and free radicals may cause neuronal damage in Parkinson disease has also led to research in ways to delay or prevent the destructive effects of these chemicals.49,60 For example, it has been suggested that certain medications might have neuroprotective effects if they control the production and harmful effects of endogenous toxins such as free radicals. Such medications are often referred to as antioxidants because they may help control oxidative stress caused by free radicals. This idea has encouraged the development and use of agents that might delay the neurodegenerative changes seen in Parkinson disease. In particular, drugs used to decrease the symptoms of Parkinson disease (dopamine agonists, selegiline, see later) as well as antioxidants such as vitamin E, have been investigated for any possible neuroprotective effects.15,30,66 To date, no agent has been identified that is overwhelmingly successful in delaying the neuronal changes occurring in Parkinson disease. Nonetheless, future research may continue to clarify the exact reason for the degeneration of substantia nigra neurons, and drugs that help prevent this degeneration could conceivably be developed to decrease or even eliminate the neuronal death that underlies the disease.

Therapeutic Agents in Parkinsonism

An overview of the drugs used to treat Parkinson disease is shown in Table 101. The primary drug used is levodopa. Other agents such as amantadine, anticholinergic drugs, catechol-O-methyltransferase


SECTION 2 Pharmacology of the Central Nervous System

Table 101
Drug Levodopa


Mechanism of Action Resolves dopamine deficiency by being converted to dopamine after crossing blood-brain barrier. Directly stimulates dopamine receptors in basal ganglia. Special Comments Still the best drug for resolving parkinsonian symptoms; long-term use limited by side effects and decreased efficacy. May produce fewer side effects (dyskinesias, fluctuations in response) than levodopa; preliminary evidence suggests that early use may also delay the progression of Parkinson disease.

Dopamine agonists Bromocriptine Cabergoline Pergolide Pramipexole Ropinirole Anticholinergics (see Table 102) Amantadine

Inhibit excessive acetylcholine influence caused by dopamine deficiency. Unclear; may inhibit the effects of excitatory amino acids in the basal ganglia.

Use in Parkinson disease limited by frequent side effects. May be used alone during early/mild stages or added to drug regimen when levodopa loses effectiveness. May improve symptoms, especially in early stages of Parkinson disease; ability to produce long-term benefits unclear. Useful as an adjunct to levodopa/carbidopa administration; may improve and prolong effects of levodopa.


Inhibits the enzyme that breaks down dopamine in the basal ganglia; enables dopamine to remain active for longer periods of time. Help prevent breakdown of dopamine in peripheral tissues; allows more levodopa to reach the brain.

COMT* inhibitors Entacapone Tolcapone

*COMT: catechol-O-methyltransferase

inhibitors, and direct-acting dopamine agonists can be used alone or in conjunction with levodopa, depending on the needs of the patient. Each of these agents is discussed below.

Because the underlying problem in Parkinson disease is a deficiency of dopamine in the basal ganglia, simple substitution of this chemical would seem to be a logical course of action. However, dopamine does not cross the blood-brain barrier. Administration of dopamine either orally or parenterally will therefore be ineffective because it will be unable to cross from the systemic circulation into the brain where it is needed. Fortunately, the immediate precursor to dopamine, dihydroxyphenylalanine (dopa; Fig. 102), crosses the blood-brain barrier quite readily. Dopa, or more specifically levodopa (the L-isomer of dopa), is able to cross the brain capillary endothelium through

an active transport process that is specific for this molecule and other large amino acids.66,71 Upon entering the brain, levodopa is then transformed into dopamine by decarboxylation from the enzyme dopa decarboxylase (Fig. 103). Administration of levodopa often dramatically improves all symptoms of parkinsonism, especially bradykinesia and rigidity. The decrease in symptoms and increase in function are remarkable in patients who respond well to the drug. As with any medication, there is a portion of the population whofor unknown reasonsdo not respond well or simply cannot tolerate the drug. Also, prolonged use of levodopa is associated with some rather troublesome and frustrating side effects (see Problems and Adverse Effects of Levodopa Therapy). However, the use of levodopa has been the most significant advancement in the management of Parkinson disease, and it remains the most effective single drug in the treatment of most patients with this disorder.32,41,52

Chapter 10 Pharmacological Management of Parkinson Disease


Tyrosine hydroxylase
Cerebral Capillary Dopamine

Capillary Endothelium (blood-brain barrier)

Cerebral Tissue


CH2 Dopa




Levodopa dopa decarboxylase Dopamine

Dopa decarboxylase

FIGURE 103 Selective permeability of the blood-brain barrier to levodopa.





FIGURE 102 Synthesis of dopamine.

Levodopa Administration and Metabolism: Use of Peripheral Decarboxylase Inhibitors

Levodopa is usually administered orally; the daily dose is determined according to each patients needs. Dosages of levodopa are also minimized by administering it with a companion drug that inhibits premature levodopa breakdown (i.e., a peripheral decarboxylase inhibitor such as carbidopa, discussed later in this section). Levodopa dosages are progressively increased until a noticeable reduction in symptoms occurs, or until side effects begin to be a problem. Daily titers are usually divided into two to three doses per day, and individual doses are often given with meals to decrease gastrointestinal irritation. Following absorption from the gastrointestinal tract, levodopa is rapidly converted to dopamine by the enzyme dopa decarboxylase. This enzyme is distributed extensively throughout the body and can be found in locations such as the liver, intestinal mucosa, kidneys, and skeletal muscle. Conversion of levodopa

to dopamine in the periphery is rather extensiveless than 1 percent of the levodopa that is administered reaches the brain in that form.66 This fact is significant because only levodopa will be able to cross the bloodbrain barrier to be subsequently transformed into dopamine. Any levodopa that is converted prematurely to dopamine in the periphery must remain there, becoming essentially useless in alleviating parkinsonism symptoms. Consequently, when given alone, rather large quantities of levodopa must be administered to ensure that enough levodopa reaches the brain in that form. This is often undesirable because the majority of the levodopa ends up as dopamine in the peripheral circulation, and these high levels of circulating dopamine can cause some unpleasant gastrointestinal and cardiovascular side effects (see the next section). An alternative method is to give levodopa in conjunction with a peripheral decarboxylase inhibitor (Fig. 104). The simultaneous use of a drug that selectively inhibits the dopa decarboxylase enzyme outside of the CNS enables more levodopa to reach the brain before being converted to dopamine. Carbidopa is a peripheral decarboxylase inhibitor that is given in conjunction with levodopa to prevent peripheral decarboxylation (see Fig. 104).48,66 Use of carbidopa with levodopa dramatically decreases the amount of levodopa needed to achieve a desired effect.48 Another decarboxylase inhibitor known as benserazide is available outside of the United States;


SECTION 2 Pharmacology of the Central Nervous System

Without Carbidopa D-C ASE Levodopa Dopamine


With Carbidopa D-C ASE Levodopa Levodopa D-C ASE Dopamine

FIGURE 104 Use of a carbidopa, a peripheral decarboxylase inhibitor, on levodopa absorption. Without carbidopa, most of the levodopa is converted to dopamine in the periphery, rendering it unable to cross the blood-brain barrier. Carbidopa inhibits the peripheral decarboxylase (D-C ase) enzyme so that levodopa can cross the bloodbrain barrier intact. Carbidopa does not cross the blood-brain barrier so that conversion of levodopa to dopamine still occurs within the CNS.

this drug can also be used to prevent peripheral conversion of levodopa to dopamine.62 Since levodopa is almost always administered along with a decarboxylase inhibitor such as carbidopa, these two drugs are often combined in the same pill and marketed under the trade name Sinemet. (Preparations of levodopa with benserazide are marketed as Madopar.) When prepared together as Sinemet, levodopa and carbidopa are combined in specific proportions, usually a fixed carbidopa-to-levodopa ratio of either 1:4 or 1:10.48 The Sinemet preparation that is typically used to initiate therapy consists of tablets containing 25 mg of carbidopa and 100 mg of levodopa. This ratio is used to achieve a rapid and effective inhibition of the dopa decarboxylase enzyme. A 10:100- or 25:250-mg preparation of carbidopa to levodopa is usually instituted as the parkinsonism symptoms become more pronounced and there is a need for larger relative amounts of levodopa. When administered with carbidopa, levodopa dosages typically begin at 200300 mg/d, and are increased periodically according to the needs of the patient. Average maintenance dosages of levodopa range between 600700 mg/d, and the maximum dosage is often 800 mg/d; however, these are highly variable from patient to patient. Levodopa-carbidopa is also available in a controlled-release preparation (Sinemet CR) that is absorbed more slowly and is intended to provide prolonged effects.48 The use of this controlled-release preparation may be helpful in patients who respond well to levodopa initially but experience dyskinesias

and fluctuations in response, such as end-of-dose akinesia and the on-off phenomenon.48 Problems related to levodopa therapy are described in the next section of this chapter.

Problems and Adverse Effects of Levodopa Therapy

Gastrointestinal Problems. Levodopa administration is often associated with nausea and vomiting. These symptoms can be quite severe, especially during the first few days of drug use. However, the incidence of this problem is greatly reduced if levodopa is given in conjunction with a peripheral decarboxylase inhibitor such as carbidopa. The reduction in nausea and vomiting when levodopa peripheral decarboxylation to dopamine is inhibited suggests that these symptoms may be caused by excessive levels of peripherally circulating dopamine. Cardiovascular Problems. Some problems with cardiac arrhythmias may arise in a patient taking levodopa. However, these problems are usually fairly minor unless the patient has a history of cardiac irregularity. Caution should be used in cardiac patients undergoing levodopa therapy, especially during exercise. Postural hypotension can also be an extremely troublesome problem in a patient taking levodopa. Again, this side effect is usually diminished when peripheral decarboxylation is inhibited and peripheral dopamine levels are not allowed to increase exces-

Chapter 10 Pharmacological Management of Parkinson Disease


sively. Still, patients undergoing physical therapy or similar regimens should be carefully observed during changes in posture and should be instructed to avoid sudden postural adjustments. This factor is especially true in patients beginning or resuming levodopa therapy. Dyskinesias. A more persistent and challenging problem is the appearance of various movement disorders in patients taking levodopa for prolonged periods. Approximately 80 percent of patients receiving chronic levodopa therapy begin to exhibit various dyskinesias such as choreoathetoid movements, ballismus, dystonia, myoclonus, and various tics and tremors.3 The specific type of movement disorder can vary from patient to patient, but tends to remain constant within the individual patient. The onset of dyskinetic side effects is particularly frustrating since levodopa ameliorates one form of the movement disorder only to institute a different motor problem. The onset of dyskinesias usually occurs after the patient has been receiving levodopa therapy for periods ranging from 3 months to several years. In some patients, these abnormal movements may simply be caused by drug-induced overstimulation of dopaminergic pathways in the basal ganglia, and decreasing the daily dosage of levodopa should help. Because levodopa has a short half-life and erratic absorption, the drug may also cause dyskinesias due to its intermittent or pulsatile stimulation of dopamine receptors.43,68 That is, the sudden rapid influx of levodopa into the brain may combine with endogenous neuronal dopamine release to cause excessive stimulation resulting in various dyskinesias.52 The reason for dyskinesias in some patients, however, may be far more complex. Certain patients, for example, may exhibit dyskinesias when plasma levodopa levels are rising or falling, or even when plasma levels are at a minimum.66 There is evidently an intricate relationship between the basal ganglia neurons that continue to release or respond to dopamine and the pharmacologic replacement of dopamine through levodopa therapy. Dyskinesias may actually be the result of functional and structural adaptations of these neurons caused by periodic fluctuations in dopamine influence supplied from exogenous sources (levodopa).7,68 Regardless of the exact neural mechanism that underlies these dyskinesias, the goal of levodopa therapy is to find a regimen that diminishes the incapacitating parkinsonism symptoms without causing other movement disorders.73 Strategies for minimizing dyskinesias include adjusting the dose of levodopa, using a

controlled-release form of this drug, and incorporating other anti-Parkinson medications into the patients drug regimen.7,68 In some patients, dyskinesias may be somewhat difficult to control because the optimal dosage of levodopa may fall into a fairly narrow range, and some of the parkinsonism symptoms may appear quite similar to the dyskinetic side effects. The physician, physical therapist, patient, and other individuals dealing with the patient should make careful observations to determine if adjustments in levodopa therapy are resulting in the desired effect. Behavioral Changes. A variety of mental side effects have been reported in patients taking levodopa. Psychotic symptoms seem especially prevalent, although depression, anxiety, and other changes in behavior have also been noted.29,57 These problems are especially prevalent in older patients or individuals who have some preexisting psychologic disturbance.48 Unlike the gastrointestinal and vascular problems described earlier, psychotic symptoms appear to be exacerbated if levodopa is used in conjunction with carbidopa. This event may be caused by greater quantities of levodopa crossing the blood-brain barrier before being converted to dopamine, thus generating higher quantities of dopamine within the brain. This idea seems logical considering that increased activity in certain dopamine pathways seems to be the underlying cause of psychosis (see Chapter 8). Treatment of these symptoms is often difficult because traditional antipsychotic medications tend to increase the symptoms of Parkinson disease. However, some of the newer atypical antipsychotics such as clozapine (Chapter 8) may help decrease psychotic symptoms without causing an increase in parkinsonism.48,77 Diminished Response to Levodopa. One of the most serious problems in levodopa therapy is that the drug seems to become less effective in many patients when it is administered for prolonged periods. When used continually for periods of 3 to 4 years, the ability of levodopa to relieve parkinsonism symptoms often progressively diminishes to the point where the drug is no longer effective.57,79 One explanation for this occurrence is that the patient develops a tolerance to the drug. A second theory is that the decreased effectiveness of levodopa may be caused by a progressive increase in the severity of the underlying disease rather than a decrease in drugs efficacy. These two theories on the decreased effectiveness of levodopa have initiated a controversy as to whether or not levodopa therapy should be started early or late in the course of Parkinson disease (see Clinical Course of Parkinson Disease: When to Use Specific Drugs).


SECTION 2 Pharmacology of the Central Nervous System

Regardless of why this occurs, the loss of levodopa efficacy can be a devastating blow to the patient who had previously experienced excellent therapeutic results from this drug. Fluctuations in Response to Levodopa. Several distinct fluctuations in the response to levodopa are fairly common in most patients.67,69,80 End-of-dose akinesia describes the phenomenon where the effectiveness of the drug simply seems to wear off prior to the next dose. This condition, known also as wearing off, is usually resolved by adjusting the quantity and timing of levodopa administration (i.e., smaller doses may be given more frequently), or by using a sustained release form of the drug. A more bizarre and less understood fluctuation in response is the on-off phenomenon. Here, the effectiveness of levodopa may suddenly and spontaneously decrease, resulting in the abrupt worsening of parkinsonism symptoms (the off period). Remission of symptoms may then occur spontaneously or after taking a dose of levodopa (the on period). This on-off pattern may repeat itself several times during the day. Although the exact reasons for this phenomenon are unclear, the off periods are directly related to diminishing plasma levels of levodopa.66 These low levels may occur when the absorption of orally administered levodopa is delayed by poor gastrointestinal motility or if levodopa must compete with large amino acids for transport across the intestinal mucosa.24 The off periods can be eliminated by administering levodopa continuously by intravenous infusion, thus preventing the fall in plasma levels. However, this is not a long-term solution, and alterations in the oral dosage schedule may have to be made in an attempt to maintain plasma levels at a relatively constant level. Specifically, the drug can be taken with smaller amounts of food and meals that are relatively low in protein so that levodopa absorption is not overwhelmed by dietary amino acid absorption. As indicated earlier, use of a controlled-release formulation such as Sinemet CR can also help alleviate various fluctuations by allowing a more steady, controlled release of levodopa into the bloodstream, thus preventing the fluctuations in plasma levodopa that seem to be responsible for the on-off phenomenon and similar problems.

effects.3 During this period, the patient is gradually removed from all anti-Parkinson medication for 3 days to 3 weeks while under close medical supervision. The purpose of the holiday is to allow the body to recover from any toxicity or tolerance that may have developed because of prolonged use of levodopa at relatively high dosages. Drug holidays are done with the hope that levodopa can eventually be resumed at a lower dosage and with better results. Drug holidays do appear to be successful in some patients with Parkinson disease. Beneficial effects may be achieved at only half of the preholiday dosage, and the incidence of side effects (such as dyskinesias, confusion, and the on-off phenomenon) may be markedly reduced.3 Despite these potential benefits, drug holidays are no longer used routinely because of their potential risk to the patient. Considering that these patients are in the advanced stages of Parkinson disease, discontinuing the anti-Parkinson medications even temporarily results in severe immobility, which can lead to problems such as venous thrombosis, pulmonary embolism, pneumonia, and other impairments that could increase morbidity and mortality.3 Hence, drug holidays may still be used on a limited basis in a few select patients with Parkinson disease, but this intervention is not used routinely at the present time.

Other Drugs Used to Treat Parkinson Disease

Dopamine Agonists
Because the basic problem in Parkinson disease is a deficiency of striatal dopamine, it would seem logical that drugs similar in function to dopamine would be effective in treating this problem. However, many dopamine agonists have serious side effects that prevent their clinical use. A few dopamine agonists such as bromocriptine (Parlodel), pergolide (Permax), and newer agents such as pramipexole (Mirapex), ropinirole (Requip), and cabergoline (Dostinex) (see Table 101) have been developed to treat Parkinson disease without causing excessive adverse effects.37,61 These dopamine agonists have traditionally been used in conjunction with levodopa, especially in patients who have begun to experience a decrease in levodopa effects, or in those who experience problems such as end-of-dose akinesia and the on-off effect.48 Simultaneous administration of levodopa with a dopamine

Drug Holidays from Levodopa

Drug holidays are sometimes used in the patient who has become refractory to the beneficial effects of levodopa or has had a sudden increase in adverse side

Chapter 10 Pharmacological Management of Parkinson Disease


agonist permits optimal results with relatively smaller doses of each drug. Dopamine agonists can also be used alone in the early stages of mild-to-moderate parkinsonism, thus providing an alternative if other anti-Parkinson drugs (including levodopa) are poorly tolerated.61,76 When used alone, dopamine agonists do not usually cause the dyskinesias and fluctuations in motor responses occurring with levodopa therapy.36,76 Several of these drugs tend to have a longer half-life than levodopa, and therefore produce a steadier and more prolonged effect on dopamine receptors.9,19 Dopamine agonists may also be more selective than levodopa in stimulating certain dopamine receptor subtypes such as the D2 receptor, thus resulting in fewer abnormal motor responses.37 Hence, these drugs continue to gain acceptance as initial treatment for patients with Parkinson disease. There is also evidence that dopamine agonists may help normalize endogenous dopamine activity, thus having a neuroprotective effect on substantia nigra neurons.61 As indicated earlier, certain medications are being investigated for their potential to delay or prevent the degeneration of dopamine-producing neurons in the basal ganglia. Dopamine agonists could produce such a neuroprotective effect by providing continuous stimulation of dopamine receptors and preventing the free radical-induced damage that is associated with abnormal dopamine synthesis and breakdown.12,86 Long-term studies should help clarify if early use of dopamine agonists is successful in slowing the progression of Parkinson disease.

Dopamine agonists may produce adverse side effects such as nausea and vomiting. Postural hypotension is also a problem in some patients. With prolonged use, these drugs may cause CNS-related side effects such as confusion and hallucinations.

Anticholinergic Drugs
As mentioned previously, the deficiency of striatal dopamine results in excessive activity in certain cholinergic pathways in the basal ganglia. Consequently, drugs that limit acetylcholine transmission are used to help alleviate the symptoms of Parkinson disease, especially tremors and rigidity. Various anticholinergic agents are available for this purpose, (Table 102), and these drugs work by blocking acetylcholine receptors in the basal ganglia.66 These drugs are fairly nonselective, however, and they tend to produce a wide variety of side effects because they block acetylcholine receptors in various tissues throughout the body (see below). When used alone, anticholinergics are usually only mildly to moderately successful in reducing symptoms and they are typically used in conjunction with levodopa or other anti-Parkinson drugs to obtain optimal results. Anticholinergics are associated with many side effects including mood change, confusion, hallucinations, drowsiness, and cardiac irregularity.13,39 In addition, blurred vision, dryness of the mouth, nausea/ vomiting, constipation, and urinary retention are fairly common. Antihistamine drugs with anticholinergic properties are also used occasionally (Table 102).

Table 102
Generic Name


Trade Name Cogentin Akineton Benadryl Parsidol Kemadrin Artane Daily Dosage (mg/d) 1.02.0 6.08.0 75200 50100 7.515.0 6.010.0 Prescribing Limit (mg/d) 6 16 300 600 20 15

Benztropine mesylate Biperiden Diphenhydramine* Ethopropazine Procyclidine Trihexyphenidyl

*Antihistamine drug with anticholinergic properties.


SECTION 2 Pharmacology of the Central Nervous System

These drugs tend to be somewhat less effective in treating parkinsonism, but appear to have milder side effects than their anticholinergic counterparts.

Amantadine (Symmetrel) was originally developed as an antiviral drug, and its ability to reduce parkinsonian symptoms was discovered by chance.18 Amantadine was being used to treat influenza in a patient with Parkinson disease, and a noticeable improvement in the patients tremor and rigidity was also observed. Since that time, amantadine has been approved for use in patients with Parkinson disease and is usually given along with levodopa. Preliminary evidence suggests that this drug may help reduce dyskinesias and other motor complications associated with levodopa therapy in people with advanced Parkinson disease.23,55,65,74 Additional research, however, is needed to confirm this effect.18 Amantadine appears to work by blocking the Nmethyl-D-aspartate (NMDA) receptor in the brain, thereby inhibiting the effects of excitatory amino acids such as glutamate.18,47 This suggests that excitatory neurotransmitters play a role in motor complications associated with advanced Parkinson disease.23,65 Future research may discover other ways of controlling these excitatory neurotransmitters, thus providing additional treatments for people with advanced Parkinson disease. The primary adverse effects associated with amantadine are orthostatic hypotension, CNS disturbance (e.g., depression, confusion, hallucinations), and patches of skin discoloration on the lower extremities (livedo reticularis). However, these side effects are relatively mild compared to those of other anti-Parkinson drugs and are usually reversed by altering the drug dosage.

to begin taking levodopa until later in the course of this disease.48 Selegiline may also be combined with levodopa therapy because selegiline prolongs the action of dopamine and allows the reduction of parkinsonism symptoms using a relatively low dose of levodopa.48 Another MAOB inhibitor, rasagiline (Azilect), has also been developed recently, and exerts effects similar to selegiline.2,85 It has been suggested that selegiline may actually slow the progression of Parkinson disease.70 Theoretically, selegiline could have neuroprotective effects because this drug inhibits dopamine oxidation, thus preventing excessive production of harmful free radicals during dopamine breakdown.15,28 Selegiline, however, may actually have neuroprotective effects that are unrelated to its effects on dopamine metabolism.70 It has been suggested, for example, that selegiline may decrease the synthesis of proteins that ultimately lead to cell death (apoptosis) in neurons that have undergone some sort of injury.27,72 Thus, administration of selegiline early in the course of Parkinson disease may help delay its progression. Nonetheless, the actual effects of this drug on disease progression remain unclear, and future studies will hopefully clarify whether early use produces long-term benefits in people with Parkinson disease. Selegiline is relatively safe in terms of short-term adverse side effects. With some MAO inhibitors, there is frequently a sudden, large increase in blood pressure if the patient ingests foods containing tyramine (see Chapter 7). However, selegiline does not appear to cause a hypertensive crisis even when such tyraminecontaining foods are eaten.48 Other side effects include dizziness, sedation, gastrointestinal distress, and headache.

Catechol-O-Methyltransferase Inhibitors
A relatively new group of drugs including entacapone (Comtan) and tolcapone (Tasmar) were developed to enhance the effects of levodopa. These drugs inhibit an enzyme known as catechol-O-methyltransferase (COMT). This enzyme converts levodopa to an inactive metabolite known as 3-O-methyldopa; hence, these drugs are referred to as COMT inhibitors.10 By preventing levodopa conversion in peripheral tissues, more levodopa is available to reach the brain and exert beneficial effects. Hence, these drugs are used as an adjunct to levodopa therapy to provide better therapeutic effects using smaller doses of levodopa.53 Evidence suggests that adding a COMT inhibitor to

Selegiline (Deprenyl, Eldepryl) is a drug that potently and selectively inhibits the monoamine oxidase type B (MAOB) enzyme. This enzyme is responsible for breaking down dopamine. By inhibiting this enzyme, selegiline prolongs the local effects of dopamine at CNS synapses. Thus, selegiline can be used alone in the early stages of Parkinson disease to prolong the effects of endogenous dopamine produced within the basal ganglia. Early administration of selegiline may alleviate motor symptoms so that patients do not need

Chapter 10 Pharmacological Management of Parkinson Disease


levodopa therapy may also reduce fluctuations in the response to levodopa, and prolong the periods of levodopa effectiveness (on time) with shorter periods of unresponsiveness (off time).53,56 The primary problem associated with COMT inhibitors is an initial increase in dyskinesias.10 This problem may be due to the fact that the COMT inhibitor is allowing more levodopa to reach the brain, and that the levodopa dosage needs to be lowered accordingly. Other side effects include nausea, diarrhea, dizziness, and muscle pain/cramps.

cian should select specific medications based on a patients individual characteristics at each stage of the disease.48

Neurosurgical Interventions in Parkinson Disease

Several innovative approaches have been studied to try to achieve a more permanent resolution to the dopamine imbalance in Parkinson disease. One approach is to surgically implant dopamine-producing cells into the substantia nigra to replace the cells that have been destroyed by the disease process.26,58 This strategy, however, is limited by several issues, including how to get a supply of viable cells. A potential source of these cells has been from fetal mesenchymal tissues. Embryonically derived stem cells have the potential to differentiate into virtually any type of human cell, thus providing a source that could be used to repair damaged tissues in many degenerative conditions including Parkinson disease.25,40 This approach, however, has generated considerable concern about the ethical use of fetal tissues for medical research and treatment. Alternative sources such as stem cells from adult bone marrow or human chromaffin cells have also been considered, but these sources might not be as effective as cells from embryonic tissues.26 Regardless of their source, there are some practical limitations associated with implanting a sufficient number of these cells into a small area deep in the brain and then keeping these cells alive and producing dopamine. Patients who would benefit from such transplants are typically older and somewhat debilitated with a possible reduction in blood flow and oxygenation of tissues deep in the brain. These facts, combined with the presence of the original pathologic process that caused Parkinson disease, may limit the transplanted tissues chances for survival. Hence, tissue transplants have not shown overwhelming clinical success, and the future of this technique as an effective and widely used method of treating Parkinson disease remains doubtful at present.58 It may be possible that new developments, including the use of cell cultures as a source of dopamine-producing cells and the use of drugs to prolong the survival of transplanted tissues, may improve the clinical outcome of this technique. Still, it remains to be seen whether tissue transplants will ever be a practical and routine method of treating the rather large number of patients with the disease.

Clinical Course of Parkinson Disease: When to Use Specific Drugs

Controversy exists as to when specific anti-Parkinson drugs should be employed.1,16 Much of the debate focuses on when levodopa therapy should be initiated. Without question, levodopa is the most effective pharmacological treatment for reducing the motor symptoms of Parkinson disease. As mentioned previously, however, long-term use of levodopa poses several risks, and the effectiveness of this drug seems to diminish after several years of use. Consequently, some practitioners question whether levodopa therapy should be withheld until the parkinsonian symptoms become severe enough to truly impair motor function. In theory, this saves the levodopa for more advanced stages of this disease, when it would be needed the most.48 Recently, some sources suggested that dopamine agonists might be a suitable alternative to levodopa as the initial treatment of Parkinson disease.1,16 Dopamine agonists can help resolve parkinsonian symptoms, sparing the use of levodopa until later in the course of the disease. As indicated, dopamine agonists may also have a reduced incidence of dyskinesias, and may slow the degeneration of substantia nigra neurons (neuroprotective effect). Thus, early use of these medications could potentially slow the progression of Parkinson disease. Levodopa can also be incorporated into the drug regimen as disability increases, along with other medications such as amantadine, anticholinergics, COMT inhibitors, and selegiline.48 There is no clear consensus of which drugs should be used in the initial and subsequent treatment of Parkinson disease. Future research should help clarify whether it is better to begin treatment with dopamine agonists, and to save levodopa and other medications until later in the disease course. Ultimately, the physi-


SECTION 2 Pharmacology of the Central Nervous System

An alternative nonpharmacological treatment involves the use of specific surgeries (pallidotomy, thalotomy) to produce lesions in specific neuronal pathways in patients with advanced Parkinson disease.82 These surgical lesions, however, are associated with many risks and side effects.50 An alternative strategy consists of surgically implanting electrodes into deep brain structures such as the globus pallidus, thalamus, and subthalamic nucleus.44,82 Highfrequency stimulation of these structures may help normalize neuronal circuitry within the basal ganglia, and help resolve the motor symptoms of advanced Parkinson disease.4,44 It is beyond the scope

of this chapter to review these newer surgical and electrical stimulation techniques. Nonetheless, these nonpharmacologic interventions continue to be developed and will hopefully provide an alternative treatment for patients who have become refractory to drug therapy during the advanced stages of the disease.82

The cause of Parkinson disease remains unknown. However, the neuronal changes that produce the symptoms associated with this movement disorder

Special Considerations for Rehabilitation

Therapists who are treating patients with Parkinson disease usually wish to coordinate the therapy session with the peak effects of drug therapy. In patients receiving levodopa, this usually occurs approximately 1 hour after a dose of the medication has been taken. If possible, scheduling the primary therapy session in elderly patients after the breakfast dose of levodopa often yields optimal effects from the standpoint of both maximal drug efficacy and low fatigue levels. Therapists working in hospitals and other institutions are sometimes faced with the responsibility of treating patients who are on a drug holiday. As discussed previously, the patient is placed in the hospital for several days and all anti-Parkinson medication is withdrawn so that the patient may recover from the adverse effects of prolonged levodopa administration. During the drug holiday, the goal of physical therapy is to maintain patient mobility as much as possible. Obviously, without anti-Parkinson drugs, this task is often quite difficult. Many patients are well into the advanced stages of the disease, and even a few days without medication can produce profound debilitating effects. Consequently, any efforts to maintain joint range of motion and cardiovascular fitness during the drug holiday are crucial in helping the patient resume activity when medications are reinstated. Therapists should also be aware of the need to monitor blood pressure in patients receiving anti-Parkinson drugs. Most of these drugs cause orthostatic hypotension, especially during the first few days treatment. Dizziness and syncope often occur because of a sudden drop in blood pressure when the patient stands up. Because patients with Parkinson disease are susceptible to falls, this problem is only increased by the chance of orthostatic hypotension. Consequently, therapists must be especially careful to guard against falls by the patient taking anti-Parkinson drugs. Finally, rehabilitation specialists should recognize that they can have a direct and positive influence on the patients health and need for drug treatment. There is consensus that an aggressive program of gait training, balance activities, and other appropriate exercises can be extremely helpful in promoting optimal health and function in patients with Parkinson disease.17,31,81 Using physical therapy and occupational therapy interventions to maintain motor function can diminish the patients need for anti-Parkinson drugs. The synergistic effects of physical rehabilitation and the judicious use of drugs will ultimately provide better results than either intervention used alone.

Chapter 10 Pharmacological Management of Parkinson Disease


Anti-Parkinson Drugs
Brief History. M.M. is a 67-year-old woman who was diagnosed with Parkinson disease 6 years ago, at which time she was treated with anticholinergic drugs (i.e., benztropine mesylate, diphenhydramine). After approximately 2 years, bradykinesia and the rigidity associated with this disease began to be more pronounced, so she was started on a combination of levodopa-carbidopa. The initial levodopa dosage was 400 mg/d. She was successfully maintained on levodopa for the next 3 years, with minor adjustments in the dosage. During that time, M.M. had been living at home with her husband. During the past 12 months, her husband noted that her ability to get around seemed to be declining, so the levodopa dosage was progressively increased to 600 mg/d. The patient was also referred to physical therapy on an outpatient basis in an attempt to maintain mobility and activities of daily living (ADL). She began attending physical therapy three times per week, and a regimen designed to maintain musculoskeletal flexibility, posture, and balance was initiated. Problem/Influence of Medication. The patient was seen by the therapist three mornings each week. After a few sessions, the therapist observed that there were certain days when the patient was able to actively and vigorously participate in the therapy program. On other days, the patient was essentially akinetic, and her active participation in exercise and gait activities was virtually impossible. There was no pattern to her good and bad days, and the beneficial effects of the rehabilitation program seemed limited by the rather random effects of her medication. The patient stated that these akinetic episodes sometimes occurred even on nontherapy days. Decision/Solution. After discussions with the patient and her husband, the therapist realized that the morning dose of levodopa was sometimes taken with a rather large breakfast. On other days, the patient consumed only a light breakfast. In retrospect, the akinetic episodes usually occurred on days when a large morning meal was consumed. The therapist surmised that this probably occurred because the large breakfast was impairing absorption of levodopa from the gastrointestinal tract. The patient was probably exhibiting the onoff phenomenon sometimes seen in patients receiving long-term levodopa therapy, which was brought on by the impaired absorption of the drug. This problem was resolved by having the patient consistently take the morning dose with a light breakfast. On mornings when the patient was still hungry, she waited 1 hour before consuming additional food to allow complete absorption of the medication. The problem was also brought to the physicians attention, and the physician prescribed a sustained release form of levodopa/carbidopa (Sinemet CR) to help provide a more continuous and prolonged absorption.

have been identified. Degeneration of dopaminergic neurons in the substantia nigra results in a deficiency of dopamine and subsequent overactivity of acetylcholine in the basal ganglia. Pharmacologic treatment attempts to rectify this dopamine-acetylcholine imbalance. Although no cure is currently available, drug therapy can dramatically improve the clinical picture in many patients by reducing the incapacitating symptoms of parkinsonism. The use of levodopa and several other medications has allowed many patients with Parkinson disease to remain active despite the diseases steadily degenerative nature. Levodopa, currently the drug of choice in treating parkinsonism, often produces remarkable

improvements in motor function. However, levodopa is associated with several troublesome side effects, and the effectiveness of this drug tends to diminish with time. Other agents, such as dopamine agonists, amantadine, selegiline, anticholinergic drugs, and COMT inhibitors, can be used alone, in combination with levodopa, or with each other to prolong the functional status of the patient. Physical therapists and other rehabilitation specialists can maximize the effectiveness of their treatments by coordinating therapy sessions with drug administration. Therapists also play a vital role in maintaining function in the patient with Parkinson disease when the efficacy of these drugs begins to diminish.

1. Ahlskog JE. Parkinsons disease: is the initial treatment established? Curr Neurol Neurosci Rep. 2003;3:289295.

2. Am OB, Amit T, Youdim MB. Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline. Neurosci Lett. 2004;355:169172.


SECTION 2 Pharmacology of the Central Nervous System 22. Dekker MC, Bonifati V, van Duijn CM. Parkinsons disease: piecing together a genetic jigsaw. Brain. 2003;126:17221733. 23. Del Dotto P, Pavese N, Gambaccini G, et al. Intravenous amantadine improves levadopa induced dyskinesias: an acute double-blind placebo-controlled study. Mov Disord. 2001; 16:515520. 24. Djaldetti R, Melamed, E. Management of response fluctuations: practical guidelines. Neurology. 1998;51 (suppl 2):S36S40. 25. Doss MX, Koehler CI, Gissel C, et al. Embryonic stem cells: a promising tool for cell replacement therapy. J Cell Mol Med. 2004;8:465473. 26. Drucker-Colin R, Verdugo-Diaz L. Cell transplantation for Parkinsons disease: present status. Cell Mol Neurobiol. 2004;24:301316. 27. Ebadi M, Sharma SK. Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinsons disease. Antioxid Redox Signal. 2003;5:319335. 28. Ebadi M, Sharma S, Shavali S, El Refaey H. Neuroprotective actions of selegiline. J Neurosci Res. 2002; 67:285289. 29. Fahn S. Description of Parkinsons disease as a clinical syndrome. Ann N Y Acad Sci. 2003;991:114. 30. Fernandez-Espejo E. Pathogenesis of Parkinsons disease: prospects of neuroprotective and restorative therapies. Mol Neurobiol. 2004;29:1530. 31. Formisano R, Pratesi L, Modarelli FT, et al. Rehabilitation and Parkinson disease. Scand J Rehabil Med. 1992;24:157160. 32. Guttman M, Kish SJ, Furukawa Y. Current concepts in the diagnosis and management of Parkinsons disease. CMAJ. 2003;168:293301. 33. Hashimoto M, Rockenstein E, Crews L, Masliah E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimers and Parkinsons diseases. Neuromolecular Med. 2003; 4:2136. 34. Hattori N, Mizuno Y. Pathogenetic mechanisms of parkin in Parkinsons disease. Lancet. 2004;364: 722724. 35. Huang Y, Cheung L, Rowe D, Halliday G. Genetic contributions to Parkinsons disease. Brain Res Brain Res Rev. 2004;46:4470. 36. Inzelberg R, Schechtman E, Nisipeanu P. Cabergoline, pramipexole and ropinirole used as monotherapy in early Parkinsons disease: an evidence-based comparison. Drugs Aging. 2003;20:847855. 37. Jenner P. Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinsons disease. Curr Opin Neurol. 2003;16(suppl 1):S3S7. 38. Jenner P. Oxidative stress in Parkinsons disease. Ann Neurol. 2003;53(suppl 3):S26S38. 39. Katzenschlager R, Sampaio C, Costa J, Lees A. Anticholinergics for symptomatic management of Parkinsons disease. Cochrane Database Syst Rev. 2003; CD003735. 40. Kim SU. Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology. 2004;24:159171.

3. Aminoff MJ. Pharmacologic management of parkinsonism and other movement disorders. In: Katzung, BG, ed. Basic and Clinical Pharmacology, 9th ed. New York: Lange Medical Books/McGraw Hill; 2004. 4. Ashkan K, Wallace B, Bell BA, Benabid AL. Deep brain stimulation of the subthalamic nucleus in Parkinsons disease 19932003: where are we 10 years on? Br J Neurosurg. 2004;18:1934. 5. Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology. 1985;35:949956. 6. Baptista MJ, Cookson MR, Miller DW. Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinsons disease. Neuroscientist. 2004;10:6372. 7. Barone P. Clinical strategies to prevent and delay motor complications. Neurology. 2003;61(suppl 3): S12S16. 8. Beal MF. Mitochondria, oxidative damage, and inflammation in Parkinsons disease. Ann N Y Acad Sci. 2003; 991:120131. 9. Bracco F, Battaglia A, Chouza C, et al. The longacting dopamine receptor agonist cabergoline in early Parkinsons disease: final results of a 5-year, doubleblind, levodopa-controlled study. CNS Drugs. 2004; 18:733746. 10. Brooks DJ. Safety and tolerability of COMT inhibitors. Neurology. 2004;62(suppl 1):S39S46. 11. Burke RE. Recent advances in research on Parkinson disease: synuclein and parkin. Neurologist. 2004;10: 7581. 12. Chalimoniuk M, Stepien A, Strosznajder JB. Pergolide mesylate, a dopaminergic receptor agonist, applied with L-DOPA enhances serum antioxidant enzyme activity in Parkinson disease. Clin Neuropharmacol. 2004;27:223229. 13. Chan DK. The art of treating Parkinson disease in the older patient. Aust Fam Physician. 2003;32:927931. 14. Chung KK, Dawson VL, Dawson TM. New insights into Parkinsons disease. J Neurol. 2003;250(suppl 3): III15III24. 15. Ciccone CD. Free-radical toxicity and antioxidant medications in Parkinson disease. Phys Ther. 1998;78: 313319. 16. Clarke CE. Neuroprotection and pharmacotherapy for motor symptoms in Parkinsons disease. Lancet Neurol. 2004;3:466474. 17. Comella CL, Stebbins GT, Brown-Toms N, Goetz CG. Physical therapy and Parkinson disease: a controlled clinical trial. Neurology. 1994;44:376378. 18. Crosby NJ, Deane KH, Clarke CE. Amantadine for dyskinesia in Parkinsons disease. Cochrane Database Syst Rev. 2003;CD003467. 19. Curran MP, Perry CM. Cabergoline: a review of its use in the treatment of Parkinsons disease. Drugs. 2004;64:21252141. 20. Dauer W, Przedborski S. Parkinsons disease: mechanisms and models. Neuron. 2003;39:889909. 21. Dawson TM, Dawson VL. Molecular pathways of neurodegeneration in Parkinsons disease. Science. 2003;302:819822.

Chapter 10 Pharmacological Management of Parkinson Disease 41. Lang AE, Obeso JA. Challenges in Parkinsons disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol. 2004;3:309316. 42. Lee SJ. Alpha-synuclein aggregation: a link between mitochondrial defects and Parkinsons disease? Antioxid Redox Signal. 2003;5:337348. 43. LeWitt PA, Nyholm D. New developments in levodopa therapy. Neurology. 2004;62(suppl 1): S9S16. 44. Lozano AM, Mahant N. Deep brain stimulation surgery for Parkinsons disease: mechanisms and consequences. Parkinsonism Relat Disord. 2004;10(suppl 1): S49S57. 45. Marin I, Lucas JI, Gradilla AC, Ferrus A. Parkin and relatives: the RBR family of ubiquitin ligases. Physiol Genomics. 2004;17:253263. 46. Mattson MP. Infectious agents and age-related neurodegenerative disorders. Ageing Res Rev. 2004;3: 105120. 47. Moresco RM, Volonte MA, Messa C, et al. New perspectives on neurochemical effects of amantadine in the brain of parkinsonian patients: a PET-[(11)C] raclopride study. J Neural Transm. 2002;109: 12651274. 48. Nelson MV, Berchou RC, LeWitt PA. Parkinson disease. In: DiPiro, JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGrawHill, NY; 2002. 49. Nomoto M. Clinical pharmacology and neuroprotection in Parkinsons disease. Parkinsonism Relat Disord. 2003;9(suppl 2):S55S58. 50. Okun MS, Vitek JL. Lesion therapy for Parkinsons disease and other movement disorders: update and controversies. Mov Disord. 2004;19:375389. 51. Olanow CW. The scientific basis for the current treatment of Parkinsons disease. Annu Rev Med. 2004;55: 4160. 52. Olanow CW, Agid Y, Mizuno Y, et al. Levodopa in the treatment of Parkinsons disease: current controversies. Mov Disord. 2004;19:9971005. 53. Olanow CW, Stocchi F. COMT inhibitors in Parkinsons disease: can they prevent and/or reverse levodopainduced motor complications? Neurology. 2004;62(suppl 1):S72S81. 54. OSuilleabhain P, Dewey RB, Jr. Movement disorders after head injury: diagnosis and management. J Head Trauma Rehabil. 2004;19:305313. 55. Paci C, Thomas A, Onofrj M. Amantadine for dyskinesia in patients affected by severe Parkinsons disease. Neurol Sci. 2001;22:7576. 56. Poewe W. The role of COMT inhibition in the treatment of Parkinsons disease. Neurology. 2004;62 (suppl 1):S31S38. 57. Rascol O, Payoux P, Ory F, et al. Limitations of current Parkinsons disease therapy. Ann Neurol. 2003; 53(suppl 3):S3S15. 58. Roitberg B, Urbaniak K, Emborg M. Cell transplantation for Parkinsons disease. Neurol Res. 2004;26: 355362. 59. Samii A, Nutt JG, Ransom BR. Parkinsons disease. Lancet. 2004;363:17831793.


60. Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA. 2004;291:358364. 61. Schwarz J. Rationale for dopamine agonist use as monotherapy in Parkinsons disease. Curr Opin Neurol. 2003;16(suppl 1):S27S33. 62. Shen H, Kannari K, Yamato H, et al. Effects of benserazide on L-DOPA-derived extracellular dopamine levels and aromatic L-amino acid decarboxylase activity in the striatum of 6-hydroxydopamine-lesioned rats. Tohoku J Exp Med. 2003;199:149159. 63. Sibon I, Tison F. Vascular parkinsonism. Curr Opin Neurol. 2004;17:4954. 64. Siderowf A, Stern M. Update on Parkinson disease. Ann Intern Med. 2003;138:651658. 65. Snow BJ, Macdonald L, Mcauley D, Wallis W. The effect of amantadine on levodopa induced dyskinesias in Parkinsons disease: a double-blind, placebo-controlled study. Clin Neuropharmacol. 2000; 23:8285. 66. Standaert DG, Young AB. Treatment of central nervous system degnerative disorders. In: Hardman, JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 67. Stocchi F. Prevention and treatment of motor fluctuations. Parkinsonism Relat Disord. 2003;9(suppl 2): S73S81. 68. Stocchi F, Olanow CW. Continuous dopaminergic stimulation in early and advanced Parkinsons disease. Neurology. 2004;62(suppl 1):S56S63. 69. Swope DM. Rapid treatment of wearing off in Parkinsons disease. Neurology. 2004;62(suppl 4): S27S31. 70. Tabakman R, Lecht S, Lazarovici P. Neuroprotection by monoamine oxidase B inhibitors: a therapeutic strategy for Parkinsons disease? Bioessays. 2004;26: 8090. 71. Tamai I, Tsuji A. Transporter-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci. 2000;89:13711388. 72. Tatton W, Chalmers-Redman R, Tatton N. Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase B. J Neural Transm. 2003;110:509515. 73. Thanvi BR, Lo TC. Long term motor complications of levodopa: clinical features, mechanisms, and management strategies. Postgrad Med J. 2004;80:452458. 74. Thomas A, Iacono D, Luciano AL, et al. Duration of amantadine benefit on dyskinesia of severe Parkinsons disease. J Neurol Neurosurg Psychiatry. 2004;75: 141143. 75. Tieu K, Ischiropoulos H, Przedborski S. Nitric oxide and reactive oxygen species in Parkinsons disease. IUBMB Life. 2003;55:329335. 76. Tintner R, Jankovic J. Dopamine agonists in Parkinsons disease. Expert Opin Investig Drugs. 2003;12: 18031820. 77. Tolosa E. Advances in the pharmacological management of Parkinson disease. J Neural Transm Suppl. 2003;64:6578.


SECTION 2 Pharmacology of the Central Nervous System 83. Warner TT, Schapira AH. Genetic and environmental factors in the cause of Parkinsons disease. Ann Neurol. 2003;53(suppl 3):S16S25. 84. Wichmann T, DeLong MR. Pathophysiology of Parkinsons disease: the MPTP primate model of the human disorder. Ann N Y Acad Sci. 2003;991: 199213. 85. Youdim MB, Bar Am O, Yogev-Falach M, et al. Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J Neurosci Res. 2005;79:172179. 86. Yuan H, Sarre S, Ebinger G, Michotte Y. Neuroprotective and neurotrophic effect of apomorphine in the striatal 6-OHDA-lesion rat model of Parkinsons disease. Brain Res. 2004;1026:95107.

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General Anesthetics
The discovery and development of anesthetic agents has been one of the most significant contributions in the advancement of surgical technique. Before the use of anesthesia, surgery was used only as a last resort and was often performed with the patient conscious, but physically restrained by several large assistants. During the past century, general and local anesthetic drugs have been used to allow surgery to be performed in a manner that is safer, that is much less traumatic to the patient, and that permits lengthier and more sophisticated surgical procedures. Anesthetics are categorized as general or local, depending on whether or not the patient remains conscious when the anesthetic is administered. General anesthetics are usually administered during the more extensive surgical procedures. Local anesthetics are given when analgesia is needed in a relatively small, well-defined area, or when the patient needs to remain conscious during surgery. The use of general anesthesia and general anesthetic agents is presented in this chapter; local anesthetics are dealt with in Chapter 12. Most physical therapists and other rehabilitation specialists are usually not involved in working with patients while general anesthesia is actually being administered. However, knowledge of how these agents work will help the therapist understand some of the residual effects that may occur when the patient is recovering from the anesthesia. This knowledge will help the therapist understand how these effects may directly influence the therapy sessions that take place during the first few days after procedures in which general anesthesia was used. be unconscious throughout the procedure and, upon awakening, have no recollection of what occurred during the surgery. An ideal anesthetic agent must be able to produce each of the following conditions: 1. Loss of consciousness and sensation. 2. Amnesia (i.e., no recollection of what occurred during the surgery). 3. Skeletal muscle relaxation (this requirement is currently met with the aid of skeletal muscle blockers used in conjunction with the anesthetic [see Neuromuscular Blockers, later]). 4. Inhibition of sensory and autonomic reflexes. 5. A minimum of toxic side effects (i.e., be relatively safe). 6. Rapid onset of anesthesia; easy adjustment of the anesthetic dosage during the procedure; and rapid, uneventful recovery after administration is terminated. Current general anesthetics meet these criteria quite well, providing that the dose is high enough to produce an adequate level of anesthesia but not so high that problems occur. The relationship between dosage and level or plane of anesthesia is discussed in the next section, Stages of General Anesthesia.

Stages of General Anesthesia

During general anesthesia, the patient goes through a series of stages as the anesthetic dosage and amount of anesthesia reaching the brain progressively increase. Four stages of anesthesia are commonly identified.39 Stage I. Analgesia. The patient begins to lose somatic sensation but is still conscious and somewhat aware of what is happening. Stage II. Excitement (Delirium). The patient is unconscious and amnesiac but appears agitated and

General Anesthesia: Requirements

During major surgery (such as laparotomy, thoracotomy, joint replacement, amputation), the patient should


SECTION 2 Pharmacology of the Central Nervous System

restless. This paradoxical increase in the level of excitation is highly undesirable because patients may injure themselves while thrashing about. Thus, an effort is made to move as quickly as possible through this stage and on to stage III. Stage III. Surgical Anesthesia. As the name implies, this level is desirable for the surgical procedure and begins with the onset of regular, deep respiration. Some sources subdivide this stage into several planes, according to respiration rate and reflex activity. 39 Stage IV. Medullary Paralysis. This stage is marked by the cessation of spontaneous respiration because respiratory control centers located in the medulla oblongata are inhibited by excessive anesthesia. The ability of the medullary vasomotor center to regulate blood pressure is also affected, and cardiovascular collapse ensues. If this stage is inadvertently reached during anesthesia, respiratory and circulatory support must be provided or the patient will die.39 Consequently, the goal of the anesthetist is to bring the patient to stage III as rapidly as possible and to maintain the patient at that stage for the duration of the surgical procedure. This goal is often accomplished by using both an intravenous and an inhaled anesthetic agent (see next section, General Anesthetic Agents: Classification and Use According to Route of Administration). Finally, the anesthetic should not be administered any longer than necessary, or recovery will be delayed. This state is often accomplished by beginning to taper off the dosage toward the end of the surgical procedure so that the patient is already recovering as surgery is completed.

inhaled agents is often used sequentially during lengthier surgical procedures.10 The intravenous drug is injected first to quickly get the patient to stage III, and an inhaled agent is then administered to maintain the patient in a stage of surgical anesthesia. Ultimately, the selection of exactly which agents will be used depends on the type and length of the surgical procedure and any possible interactions with other anesthetics or medical problems of the patient. Specific injected and inhaled anesthetics are presented here.

General Anesthetics: Specific Agents

Inhalation Anesthetics
Anesthetics administered by this route exist either as gases or as volatile liquids that can be easily mixed with air or oxygen and then inhaled by a patient. When administered, a system of tubing and valves is usually employed to deliver the anesthetic drug directly to the patient through an endotracheal tube or a mask over the face (Figure 111). This delivery system offers the obvious benefit of focusing the drug on the patient without anesthetizing everyone else in the room. These systems also allow for easy adjustment of the rate of delivery and concentration of the inhaled drug. Inhaled anesthetics currently in use include halogenated volatile liquids such as desflurane, enflurane, halothane, isoflurane, methoxyflurane, and sevoflurane (Table 111). These volatile liquids are all chemically similar, but newer agents such as desflurane and sevoflurane are often used preferentially because they permit a more rapid onset, a faster recovery, and better control during anesthesia compared to older agents such as halothane.9,15 These volatile liquids likewise represent the primary form of inhaled anesthetics. The only gaseous anesthetic currently in widespread use is nitrous oxide, which is usually reserved for relatively short-term procedures (e.g., tooth extractions). Earlier inhaled anesthetics, such as ether, chloroform, and cyclopropane, are not currently used because they are explosive in nature or produce toxic effects that do not occur with the more modern anesthetic agents.

General Anesthetics: Classification and Use According to Route of Administration

Specific agents are classified according to the two primary routes of administrationintravenous or inhaled.11,39 Intravenously injected anesthetics offer the advantage of a rapid onset, thus allowing the patient to pass through the first two stages of anesthesia very quickly. The primary disadvantage is that there is a relative lack of control over the level of anesthesia if too much of the drug is injected. Inhaled anesthetics provide an easier method of making adjustments in the dosage during the procedure, but it takes a relatively long time for the onset of the appropriate level of anesthesia. Consequently, a combination of injected and

Intravenous Anesthetics
When given in appropriate doses, several categories of central nervous system (CNS) depressants can serve as
Text continued on page 139

Chapter 11

General Anesthetics
(From Brown BR. Pharmacology of general anesthesia. In: Clark WG, Brater DC, and Johnson AR. Goths Medical Pharmacology. 13th ed. St Louis: CV Mosby; 1992: 385, with permission.)


3 4

FIGURE 111 Schematic diagram of a closed anesthesia system. (1) Vaporizer for volatile liquid anesthetics. (2) Compressed gas source. (3) Inhalation unidirectional valve. (4) Mask. (5) Unidirectional exhalation valve. (6) Rebreathing bag. (7) Carbon dioxide absorption chamber.

Table 111

Representative Structure Inhaled Anesthetics

Volatile liquids Desflurane (Suprane) Enflurane (Ethrane) Halothane (Fluothane) Isoflurane (Forane) Methoxyflurane (Penthrane) Sevoflurane (Ultane)




Gas Nitrous oxide (nitrogen monoxide)



Nitrous oxide

Intravenous Anesthetics Barbiturates Methohexital (Brevital sodium) Thiopental (Pentothal)

S C N H C O Thiopental H N O C C CH (CH2)2 CH3 C2H5

(Continued on following page)


SECTION 2 Pharmacology of the Central Nervous System

Table 111


Representative Structure

Benzodiazepines Diazepam (Valium) Lorazepam (Ativan) Midazolam (Versed)


Opioids Butorphanol (Stadol) Fentanyl derivatives (Sublimaze, others) Hydromorphone (Dilaudid, Hydrostat) Levorphanol (Levo-Dromoran) Meperidine (Demerol) Morphine (many trade names) Nalbuphine (Nubain) Oxymorphone (Numorphan) Pentazocine (Talwin) Etomidate (Amidate)


N CH3 Meperidine




Ketamine (Ketalar)


HN CH3 Ketamine O

Propofol (Diprivan)

CH(CH3)2 OH CH(CH3)2 Propofol

Chapter 11

General Anesthetics


general anesthetics (see Table 111).38,39 Barbiturate drugs such as thiopental, thiamylal, and methohexital have been used commonly to induce anesthesia in many situations. Barbiturates are noted for their fast onset (when administered intravenously) and relative safety when used appropriately. Several other types of drugs including benzodiazepines (diazepam, lorazepam, midazolam) and opioid analgesics (fentanyl, morphine, meperidine) have also been used to induce or help maintain general anesthesia. Although these other agents are often used as preoperative sedatives, larger doses can be used alone or in combination with other general anesthetics to produce anesthesia in short surgical or diagnostic procedures, or where other general anesthetics may be contraindicated (e.g., cardiovascular disease). Another intravenous general anesthetic is ketamine (Ketalar). This agent produces a somewhat different type of condition known as dissociative anesthesia.16,39 This term is used because of the clinical observation that the patient appears detached or dissociated from the surrounding environment. The patient appears awake but is sedated and usually unable to recall events that occurred when the ketamine was in effect. Dissociative anesthesia is useful during relatively short diagnostic or surgical procedures (e.g., endoscopy) or during invasive procedures in children or certain high-risk patients (e.g., some older adults or people with low blood pressure or bronchospastic disease).11,16 A similar type of anesthesia is produced by combining the opioid fentanyl with the antipsychotic drug droperidol. The combination of these two agents produces a condition known as neuroleptanalgesia, which is also characterized by a dissociation from what is happening around the patient, with or without loss of consciousness.39 An inhaled anesthetic such as nitrous oxide can also be added to convert neuroleptanalgesia to neuroleptanesthesia.39 Neuroleptanalgesia and neuroleptanesthesia are typically used for short surgical procedures, including endoscopy or burn dressings, or for patients who are seriously ill and may not tolerate general anesthesia using more conventional methods. Finally, newer intravenous anesthetics such as etomidate (Amidate) and propofol (Diprivan) are available. Etomidate is a hypnoticlike drug that causes a rapid onset of general anesthesia with a minimum of cardiopulmonary side effects. Hence, this drug may be useful in patients with compromised cardiovascular or respiratory function. Propofol is a short-acting hypnotic that is useful as a general anesthetic in some

short invasive procedures, or to maintain anesthesia in longer procedures.22 Recovery from propofol may also be more rapid than with other anesthetics, making this drug useful when early mobilization of the patient is desirable.38

Following either injection or inhalation administration, general anesthetics become widely and uniformly distributed throughout the body, largely because of their high degree of lipid solubility. As a result, a great deal of the anesthetic may become temporarily stored in adipose tissues and slowly washed out when the patient is recovering from surgery. If the person was anesthetized for an extended period of time and has large deposits of fat, this washout may take quite some time.11,17 During this period, symptoms such as confusion, disorientation, and lethargy may occur, presumably because the drug is being redistributed to the CNS. The patients age also influences anesthetic requirements and distribution, with older individuals usually requiring less anesthetic for a given procedure.29 Since older people need smaller concentrations of anesthetic, the chance that more anesthetic may be administered during surgery than is needed is increased and recovery will be somewhat delayed. Depending on the individual drug, elimination occurs primarily through excretion from the lungs, biotransformation in the liver, or a combination of these two methods.39 If the patient has any pulmonary or hepatic dysfunction, elimination of the anesthetic will be further delayed.

Mechanisms of Action
Although general anesthetics have been used extensively for over 150 years, debate still exists as to exactly how these drugs work. Clearly these drugs are able to inhibit the neuronal activity throughout the CNS. It appears that they can decrease activity of neurons in the reticular activating system in the brain, and this action explains their ability to produce unconsciousness and lack of memory (amnesia) during surgery.7 General anesthetics likewise inhibit neuronal function in the spinal cord, and this action explains their ability to produce immobility and inhibit motor responses to painful stimuli.7


SECTION 2 Pharmacology of the Central Nervous System

The exact way in which these drugs affect these neurons remains somewhat speculative. In the past, it was believed that general anesthetics primarily affected the lipid bilayer of CNS neurons. This so-called general perturbation theory was based on the premise that general anesthetic molecules become dissolved directly in the nerve membranes lipid bilayer and serve to generally perturb membrane function by increasing membrane fluidity and disrupting the phospholipid environment that surrounds the protein channel.7 Membrane excitability would be decreased because ion channels, including sodium channels, are unable to open and allow the influx of sodium needed to initiate an action potential (Fig. 112). The primary support for the membrane perturbation theory was the direct correlation between anesthetic potency and lipid solubility,39 meaning that the more easily the drug dissolves in the bilayer, the less is needed to achieve a given level of anesthesia. This theory was further supported by the fact that general anesthetics all produce a similar effect, even though they have quite diverse chemical structures (see Table 111). Presumably, if drugs bind to a certain type of receptor, they should share some structural similarities. More recent evidence, however, suggests that general anesthetics bind to specific receptors located

on the outer surface of CNS neurons.7,14 In particular, many general anesthetics bind to CNS receptors that are specific for gamma-aminobutyric acid (GABA). As discussed in Chapter 6, GABA receptors contain a chloride ion channel that, when activated by GABA, increases influx of chloride ions into the neuron, thereby inhibiting that neuron. By binding to specific GABA receptors (the GABAA subtype), general anesthetics increase the effects of GABA, thus enhancing CNS inhibition throughout the CNS.27,28 This widespread CNS inhibition ultimately leads to a state of general anesthesia. Hence, many general anesthetics exert their primary effects by binding to inhibitory GABAA receptors in the brain and cord. This fact seems true for both the commonly used intravenous anesthetics (barbiturates, benzodiazepines, propofol, etomidate) as well as the typical inhaled forms (halothane, enflurane, sevoflurane).19 Some of their anesthetic effects, however, might also be mediated by other receptors. Many general anesthetics, for example, also bind to excitatory acetylcholine receptors on CNS neurons, and inhibit the function of these receptors. This combination of increased inhibition (through GABA receptors) and decreased excitation (through acetylcholine receptors) would certainly explain why

No Drug
(Na channel shown open)

(Na+ channel closed)

A. General Perturbation Theory



B. Specific Receptor Theory

FIGURE 112 Schematic illustration of two possible ways general anesthetics may act on the nerve membrane. In the general perturbation theory, anesthetic molecules lodge in the lipid bilayer and inhibit sodium channel function by disrupting membrane structure. In the specific receptor theory, anesthetics inhibit the opening of the sodium channel by binding directly to the channel protein.

Chapter 11

General Anesthetics


these drugs are so effective in reducing the level of consciousness and excitability throughout the brain and cord.34,41 In addition to GABA and acetylcholine receptors, other CNS receptors have been implicated in mediating the effects of specific general anesthetics. Opioids, for example, decrease transmission in nociceptive pathways by binding to specific presynaptic and postsynaptic opioid receptors in the brain and spinal cord (see Chapter 14). Injected anesthetics such as ketamine, and certain inhaled agents (nitrous oxide), bind to the N-methyl-D-aspartate (NMDA) receptor in the brain, thus inhibiting the excitatory effects of glutamate.34,41 Other proteins that might be affected by anesthetics include serotonin receptors and ion channels that are specific for sodium, potassium, or calcium.7,35. Hence, it is believed that general anesthetics exert most, if not all, of their effects by binding to one or more neuronal receptors in the CNS. This idea is a departure from the general perturbation theory described earlier; that is, that the inhaled anesthetics affected the lipid bilayer rather than a specific protein. Continued research will continue to clarify the mechanism of these drugs, and future studies may lead to more agents that produce selective anesthetic effects by acting at specific receptor sites in the brain and spinal cord.

offer the dual advantage of producing sedation and reducing vomiting (antiemesis). Antacids and other drugs that increase gastric pH are sometimes used to decrease stomach acidity and thus reduce the risk of serious lung damage if gastric fluid is aspirated during general surgery. Preoperative administration of an anti-inflammatory steroid (dexamethasone) can likewise help control postoperative symptoms such as pain and vomiting.4,12 In the past, anticholinergics (atropine, scopolamine) were administered to help reduce bronchial secretions and aid in airway intubation. However, anesthetics currently in use do not produce excessive airway secretions (as did prior agents), so the preoperative use of anticholinergics is no longer critical.11

Neuromuscular Blockers
Skeletal muscle paralysis is essential during surgical procedures. The patient must be relaxed to allow proper positioning on the operating table and to prevent spontaneous muscle contractions from hampering the surgery.23,24 Imagine the disastrous effects that a muscular spasm in the arm would have on a delicate procedure such as nerve repair or limb reattachment. Neuromuscular paralysis also makes it easier for the patient to be ventilated mechanically because the thoracic wall is more compliant and does not offer as much resistance to mechanical inflation and deflation of the chest cavity. Hence, these drugs are used as an adjunct to general anesthesia as well as in other situations that require mechanical ventilation (intensive care units). Most currently used general anesthetics also produce skeletal muscle relaxation, but it takes a larger dose of the anesthetic to produce adequate muscular relaxation than is needed to produce unconsciousness and amnesia; that is, the patient must be well into stage III and almost into stage IV of anesthesia before muscle paralysis is complete. Consequently, a drug that blocks the skeletal neuromuscular junction is given in conjunction with a general anesthetic to allow the use of a lower dose of anesthetic while still ensuring skeletal muscle paralysis. These drugs work by blocking the postsynaptic acetylcholine receptor located at the skeletal neuromuscular junction. Several different neuromuscular blockers are currently available, and the choice of a specific agent depends primarily on the desired length of action and the agents potential side effects (Table 113).21,23 Possible side effects include cardiovascular problems (tachycardia), increased histamine release, increased

Adjuvants in General Anesthesia

Preoperative Medications
Frequently, a preoperative sedative is given to a patient 1 to 2 hours before the administration of general anesthesia.2,36 Sedatives are usually administered orally or by intramuscular injection, and are given while the patient is still in his or her room. This approach serves to relax the patient and reduce anxiety when arriving at the operating room. Commonly used preoperative sedatives include barbiturates (secobarbital, pentobarbital), opioids (butorphanol, meperidine), and benzodiazepines (diazepam, lorazepam) (Table 112). Different sedatives are selected depending on the patient, the type of general anesthesia used, and the preference of the physician. A number of other medications may be used preoperatively to achieve various goals (see Table 112).5,40 Antihistamines (promethazine, hydroxyzine)


SECTION 2 Pharmacology of the Central Nervous System

Table 112
Classification Barbiturates


Preoperative Indication Decrease anxiety; facilitate induction of anesthesia Drug Amobarbital Butabarbital Pentobarbital Phenobarbital Secobarbital Method of Administration* Oral: 200 mg 1 to 2 hours before surgery Oral: 50100 mg 60 to 90 minutes before surgery Oral: 100 mg IM: 150200 mg IM: 130200 mg 60 to 90 minutes before surgery Oral: 200300 mg 1 to 2 hours before surgery IV: 2 mg 6090 minutes before surgery IM: 12.2 mg/kg body weight (100 mg maximum) 30 to 90 minutes before surgery IM: 50100 mg 1 hour before surgery IM or IV: 510 mg prior to surgery IM: 0.05 mg/kg body weight (4 mg maximum) 2 hours before surgery IV: 0.0440.05 mg/kg body weight (4 mg maximum) 15 to 20 minutes before surgery Oral: 50 mg 20 to 30 minutes before surgery Oral: 50100 mg Oral: 2 mg IM: 0.20.6 mg 30 to 60 minutes before surgery IM: 0.0044 mg/kg body weight 30 to 60 minutes before induction of anesthesia IM: 0.20.6 mg 30 to 60 minutes before induction of anesthesia


Provide analgesic, antianxiety, and sedative effects

Butorphanol Meperidine


Decrease anxiety and tension; provide sedation and amnesia


Diazepam Lorazepam


Provide sedative-hypnotic effects

Diphenhydramine Hydroxyzine


Prevent excessive salivation and respiratory tract secretions




*Typical adult doses. IV, intravenous; IM, intramuscular. **Virtually all opioids can be used as a preoperative medication. Selection of a specific type and dose can be individualized based on the needs of each patient.

Chapter 11

General Anesthetics


Classification Antacids (H2 receptor blockers)

Preoperative Indication Reduce gastric acidity; help prevent aspiration pneumonitis

Drug Cimetidine

Method of Administration* IM: 300 mg 1 hour before induction of anesthesia; 300 mg every 4 hours until patient responds to commands IM: 50 mg 45 to 60 minutes before induction of anesthesia


plasma potassium levels (hyperkalemia), residual muscle pain and weakness, and immunologic reactions (anaphylaxis).13,25 Selection of a specific agent is therefore designed to minimize the risk of a certain side effect in a specific patient; for example, a drug that produces relatively little cardiovascular effects would be selected for a patient with cardiovascular disease. Efforts are also made to use small doses of relatively short-acting agents so that the length of muscle paralysis is kept to a minimum.6 The paralytic effects of these agents should disappear by the end of the surgical procedure. If necessary, drugs such as neostigmine or edrophonium can also be administered to help reverse the effects of neuromuscular blockade.24,30 These drugs inhibit the enzyme that breaks

down acetylcholine (the acetylcholinesterase), thereby prolonging its effects and hastening recovery of motor function. The pharmacology of acetylcholinesterase inhibitors is addressed in more detail in Chapter 19. Nonetheless, residual effects of the neuromuscular blocker can persist in some patients long after surgery is complete.6,13 The most serious complication is residual paralysis; that is, skeletal muscle contraction remains depressed for several hours after the drug should have worn off.8,18 In extreme cases, this residual paralysis necessitates that the patient remain in intensive care with a mechanical ventilator to provide respiratory support. It is not always clear why certain patients do not recover adequately from neuromuscular blockade. In

Table 113
Generic Name Nondepolarizing blockers Tubocurarine Atracurium Doxacurium Mivacurium Pancuronium Pipecuronium Rapacuronium Rocuronium Vecuronium


Trade Name Time of Onset (min)* Clinical Duration (min) Relative Duration

Tracrium Nuromax Mivacron Pavulon Arduan Raplon Zemuron Norcuron

46 24 46 24 46 24 12 12 24

80120 3060 90120 1218 120180 80100 1530 3060 6090

Long Intermediate Long Short Long Long Intermediate Intermediate Intermediate

Depolarizing blockers Succinylcholine

Anectine, others




*Reflects usual adult intravenous dose. Source: Adapted from Taylor.37


SECTION 2 Pharmacology of the Central Nervous System

some cases, the residual effects are attributed to genetic differences in the enzymes responsible for metabolizing the neuromuscular blocker.37 If these enzymes are deficient or absent, the patient cannot adequately metabolize the blocker, hence paralysis continues for days or even weeks. In other patients, residual effects may occur if the patient has a concurrent neuromuscular condition such as a spinal cord injury, peripheral neuropathies, intracranial lesions, or muscle pathologies.26,32 Efforts should be made to use these drugs sparingly, and to check that their effects have worn off before the patient leaves the operating room. In fact, electric stimulation of a peripheral nerve (e.g., ulnar nerve) can be used to objectively determine if there is residual muscle paralysis.1 The muscles supplied by the nerve must show an appropriate twitch response to a given electric stimulus to insure that the patient has recovered adequately from the neuromuscular blocking drug.20,31 It should also be realized that neuromuscular junction blockers are an adjunct to general anesthesia but that these blockers do not cause anesthesia or analgesia when used alone.26,33 The patient must receive an adequate amount of the general anesthetic throughout the surgery when a neuromuscular junction blocker is used. This idea is critical considering that the patient will be paralyzed by the neuromuscular junction blocker and unable to respond to painful stimuli if the anesthesia is inadequate. Failure to provide adequate anesthesia has resulted in some harrowing reports from patients who were apparently fully awake during surgery but unable to move or cry out.26,33 Two general types of neuromuscular blockers are discussed here. They are classified according to those that depolarize the skeletal muscle cell when binding to the cholinergic receptor and those that do not.37 Nondepolarizing Blockers. These drugs act as competitive antagonists of the postsynaptic receptor; that is, they bind to the receptor but do not activate it (see Chapter 4). This binding prevents the agonist (acetylcholine) from binding to the receptor; the result is paralysis of the muscle cell. These drugs all share a structural similarity to curare (the first neuromuscular blocker), which explains their affinity and relative selectivity for the cholinergic receptor at the skeletal neuromuscular junction. Specific agents, their onset, and duration of action are listed in Table 113.

Depolarizing Blockers. Although these drugs also inhibit transmission at the skeletal neuromuscular junction, their mechanism is different from that of the nondepolarizing agents. These drugs initially act like acetylcholine by binding to and stimulating the receptor, resulting in depolarization of the muscle cell. However, the enzymatic degradation of the drug is not as rapid as the destruction of acetylcholine, so the muscle cell remains depolarized for a prolonged period. While depolarized, the muscle is unresponsive to further stimulation. The cell must become repolarized, or reprimed, before the cell will respond to a second stimulus. This event is often referred to as phase I blockade.37 If the depolarizing blocker remains at the synapse, the muscle cell eventually repolarizes, but it will remain unresponsive to stimulation by acetylcholine. This occurrence is referred to as phase II blockade and is believed to occur because the drug exerts some sort of modification on the receptor. This modification could be in the form of a temporary change in the receptors shape. Clinically, when these drugs are first administered, they are often associated with a variable amount of muscle tremor and fasciculation (because of the initial depolarization), but this is followed by a period of flaccid paralysis. Although several drugs that act as depolarizing blockers are available, the only agent currently in clinical use is succinylcholine (see Table 113).37

General anesthesia has been used for some time to permit surgical procedures of various types and durations. Several different effective agents are currently available and are relatively safe in producing a suitable anesthetic condition in the patient. General anesthetics are classified according to their two primary routes of administration: inhalation and intravenous infusion. Specific anesthetic agents and anesthetic adjuvants (preoperative sedatives, neuromuscular blockers, etc.) are primarily selected according to the type of surgical procedure being performed and the overall condition of the patient. Health professionals should be cognizant of the fact that their patients may take some time to fully recover from the effects of general anesthesia and should adjust their postoperative care accordingly.

Chapter 11

General Anesthetics


Special Concerns in Rehabilitation

A rehabilitation specialist is most likely to encounter major problems when the patient is not quite over the effects of the anesthesia. Dealing with a patient the day after surgery or even on the same day might be difficult because he or she is woozy. Some anesthetics may produce confusion or psychoticlike behavior (delirium) during the recovery period, especially in older adults.3 Muscle weakness may also occur for a variable amount of time, especially if a neuromuscular blocker was used during the surgical procedure. Of course, patients who are in relatively good health and who have had relatively short or minor surgeries will have minimal residual effects. However, patients who are debilitated or who have other medical problems impairing drug elimination may continue to show some anesthesia aftereffects for several days.3 These problems should disappear with time, so the therapist must plan activities accordingly until recovery from the anesthetic is complete. Another problem that therapists frequently deal with is the tendency for bronchial secretions to accumulate in the lungs of patients recovering from general anesthesia. General anesthetics depress mucociliary clearance in the airway, leading to a pooling of mucus, which may produce respiratory infections and atelectasis. Therapists play an important role in preventing this accumulation by encouraging the patients early mobilization and by implementing respiratory hygiene protocols (i.e., breathing exercises and postural drainage).

General Anesthetics
Brief History. B.W., a 75-year-old woman, fell at home and experienced a sudden sharp pain in her left hip. She was unable to walk and was taken to a nearby hospital where x-ray examination showed an impacted fracture of the left hip. The patient was alert and oriented at the time of admission. She had a history of arteriosclerotic cardiovascular disease and diabetes mellitus, but her medical condition was stable. The patient was relatively obese, and a considerable amount of osteoarthritis was present in both hips. Two days after admission, a total hip arthroplasty was performed under general anesthesia. Meperidine (Demerol) was given intramuscularly as a preoperative sedative. General anesthesia was induced by intravenous administration of thiopental (Pentothal) and sustained by inhalation of halothane (Fluothane). The surgery was completed successfully, and physical therapy was initiated at the patients bedside on the subsequent day. Problem/Influence of Medication. At the initial therapy session, the therapist found the patient to be extremely lethargic and disoriented. She appeared confused about recent events and was unable to follow most commands. Apparently, she was experiencing some residual effects of the general anesthesia. Decision/Solution. The patients confusion and disorientation precluded any activities that required her cooperation, including any initial attempts at weight-bearing exercises. The therapist limited the initial session to passiveand active-assisted exercises of both lower extremities. Active upper-extremity exercises were encouraged within the limitations of the patients ability to follow instructions. These exercises were instituted to help increase metabolism and excretion of the remaining anesthesia. The patient was also placed on a program of breathing exercises in an effort to facilitate excretion of the anesthesia, as well as to maintain respiratory function and prevent the accumulation of mucus in the airways. As the patients mental disposition gradually improved, the therapist initiated partial weight bearing in the parallel bars. From there, the patient progressed to a walker and was soon able to ambulate independently using the device. Within 1 week after the surgery, no overt residual effects of the anesthesia were noted, and the remainder of the hospital stay was uneventful.


SECTION 2 Pharmacology of the Central Nervous System after reversal with pyridostigmine. Anesth Analg. 2002; 95:16561660. Kitamura A, Sato R, Marszalec W, et al. Halothane and propofol modulation of gamma-aminobutyric acid A receptor single-channel currents. Anesth Analg. 2004;99:409415. Kopman AF, Kopman DJ, Ng J, Zank LM. Antagonism of profound cisatracurium and rocuronium block: the role of objective assessment of neuromuscular function. J Clin Anesth. 2005;17:3035. Lee C. Conformation, action, and mechanism of action of neuromuscular blocking muscle relaxants. Pharmacol Ther. 2003;98:143169. Marik PE. Propofol: therapeutic indications and sideeffects. Curr Pharm Des. 2004;10:36393649. McManus MC. Neuromuscular blockers in surgery and intensive care, part 1. Am J Health Syst Pharm. 2001;58:22872299. McManus MC. Neuromuscular blockers in surgery and intensive care, part 2. Am J Health Syst Pharm. 2001;58:23812395. Mertes PM, Laxenaire MC. Adverse reactions to neuromuscular blocking agents. Curr Allergy Asthma Rep. 2004;4:716. Messahel FM, Al-Qahtani AS. Awareness during surgery. Saudi Med J. 2003;24:967970. Rudolph U, Antkowiak B. Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci. 2004;5:709720. Rudolph U, Mohler H. Analysis of GABA A receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol. 2004; 44:475498. Sadean MR, Glass PS. Pharmacokinetics in the elderly. Best Pract Res Clin Anaesthesiol. 2003;17:191205. Saitoh Y, Hattori H, Sanbe N, et al. Reversal of vecuronium with neostigmine in patients with diabetes mellitus. Anaesthesia. 2004;59:750754. Samet A, Capron F, Alla F, et al. Single acceleromyographic train-of-four, 100 Hertz tetanus or doubleburst stimulation: which test performs better to detect residual paralysis? Anesthesiology. 2005; 102:5156. Schreiber JU, Mencke T, Biedler A, et al. Postoperative myalgia after succinylcholine: no evidence for an inflammatory origin. Anesth Analg. 2003;96: 16401644. Sigalovsky N. Awareness under general anesthesia. AANA J. 2003;71:373379. Sloan TB. Anesthetics and the brain. Anesthesiol Clin North America. 2002;20:265292. Sonner JM, Antognini JF, Dutton RC, et al. Inhaled anesthetics and immobility: mechanisms, mysteries, and minimum alveolar anesthetic concentration. Anesth Analg. 2003;97:718740. Tamura M, Nakamura K, Kitamura R, et al. Oral premedication with fentanyl may be a safe and effective alternative to oral midazolam. Eur J Anaesthesiol. 2003;20:482486.

1. Baykara N, Solak M, Toker K. Predicting recovery from deep neuromuscular block by rocuronium in the elderly. J Clin Anesth. 2003;15:328333. 2. Bauer KP, Dom PM, Ramirez AM, OFlaherty JE. Preoperative intravenous midazolam: benefits beyond anxiolysis. J Clin Anesth. 2004;16:177183. 3. Bekker AY, Weeks EJ. Cognitive function after anaesthesia in the elderly. Best Pract Res Clin Anaesthesiol. 2003;17:259272. 4. Bisgaard T, Klarskov B, Kehlet H, Rosenberg J. Preoperative dexamethasone improves surgical outcome after laparoscopic cholecystectomy: a randomized double-blind placebo-controlled trial. Ann Surg. 2003;238: 651660. 5. Chia YY, Lo Y, Liu K, et al. The effect of promethazine on postoperative pain: a comparison of preoperative, postoperative, and placebo administration in patients following total abdominal hysterectomy. Acta Anaesthesiol Scand. 2004;48:625630. 6. Cammu G. Postoperative residual curarisation: complication or malpractice? Acta Anaesthesiol Belg. 2004;55:245249. 7. Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N Engl J Med. 2003;348:21102124. 8. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology. 2003;98:1042 1048. 9. Eger EI, 2nd. Characteristics of anesthetic agents used for induction and maintenance of general anesthesia. Am J Health Syst Pharm. 2004;61(suppl 4):S3S10. 10. Eger EI, White PF, Bogetz MS. Clinical and economic factors important to anaesthetic choice for day-case surgery. Pharmacoeconomics. 2000;17:245262. 11. Elhakim M, Ali NM, Rashed I, et al. Dexamethasone reduces postoperative vomiting and pain after pediatric tonsillectomy. Can J Anaesth. 2003;50:392397. 12. Eriksson LI. Residual neuromuscular blockade. Incidence and relevance. Anaesthesist. 2000;49(suppl 1): S18S19. 13. Evers AS, Crowder CM. General anesthetics. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 14. Friederich P. Basic concepts of ion channel physiology and anaesthetic drug effects. Eur J Anaesthesiol. 2003;20:343353. 15. Golembiewski J. Considerations in selecting an inhaled anesthetic agent: case studies. Am J Health Syst Pharm. 2004;61(suppl 4):S10S17. 16. Ivani G, Vercellino C, Tonetti F. Ketamine: a new look to an old drug. Minerva Anestesiol. 2003;69:468471. 17. Joshi GP. Inhalational techniques in ambulatory anesthesia. Anesthesiol Clin North America. 2003;21: 263272. 18. Kim KS, Lew SH, Cho HY, Cheong MA. Residual paralysis induced by either vecuronium or rocuronium 19.


21. 22. 23. 24. 25. 26. 27. 28.

29. 30. 31.


33. 34. 35.


Chapter 11 General Anesthetics 37. Taylor P. Agents acting at the neuromuscular junction and autonomic ganglia. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001. 38. Tesniere A, Servin F. Intravenous techniques in ambulatory anesthesia. Anesthesiol Clin North America. 2003;21:273288. 39. Trevor AJ, White PF. General anesthetics. In: Katzung BG, ed. Basic and Clinical Pharmacology. 9th


ed. New York: Lange Medical Books/McGraw-Hill; 2004. 40. Turner KE, Parlow JL, Avery ND, et al. Prophylaxis of postoperative nausea and vomiting with oral, longacting dimenhydrinate in gynecologic outpatient laparoscopy. Anesth Analg. 2004;98:16601664. 41. Villars PS, Kanusky JT, Dougherty TB. Stunning the neural nexus: mechanisms of general anesthesia. AANA J. 2004;72:197205.

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Local Anesthetics
Local anesthesia produces a loss of sensation in a specific body part or region. Frequently this application occurs before performing a relatively minor surgical procedure. This approach involves introducing an anesthetic drug near the peripheral nerve that innervates the desired area. The basic goal is to block afferent neural transmission along the peripheral nerve so that the procedure is painless. When a local anesthetic is introduced in the vicinity of the spinal cord, transmission of impulses may be effectively blocked at a specific level of the cord, allowing more extensive surgical procedures to be performed (e.g., caesarean delivery) because a larger region of the body is being anesthetized. This approach, however, is still considered a local anesthetic because the drug acts locally at the spinal cord and the patient remains conscious during the surgical procedure. Using a local anesthetic during a surgical procedure offers several advantages over the use of general anesthesia, including a relatively rapid recovery and lack of residual effects.13,15 There is a virtual absence of the postoperative confusion and lethargy often seen after general anesthesia. In most cases of minor surgery, patients are able to leave the practitioners office or hospital almost as soon as the procedure is completed. In more extensive procedures, local anesthesia offers the advantage of not interfering with cardiovascular, respiratory, and renal functioning. This fact can be important in patients with problems in these physiological systems. During childbirth, local (spinal) anesthesia imposes a lesser risk to the neonate than general anesthesia.14,41 The primary disadvantages of local anesthesia are the length of time required to establish an anesthetic effect and the risk that analgesia will be incomplete or insufficient for the respective procedure.47 The latter problem can usually be resolved by administering more local anesthesia if the procedure is relatively minor, or by switching to a general anesthetic during a major procedure in the event of an emergency arising during surgery. In nonsurgical situations, local anesthetics are sometimes used to provide analgesia. These drugs may be used for short-term pain relief in conditions such as musculoskeletal and joint pain (e.g., bursitis, tendinitis), or in more long-term situations such as pain relief in cancer or treatment of chronic pain. In addition, local anesthetics may be used to block efferent sympathetic activity in conditions such as reflex sympathetic dystrophy syndrome. During these nonsurgical applications, physical therapists and other rehabilitation personnel will often be directly involved in treating the patient while the local anesthetic is in effect. If prescribed by a physician, the local anesthetic may actually be administered by the physical therapist via phonophoresis or iontophoresis. Consequently, these individuals should have adequate knowledge of the pharmacology of local anesthetics.

Types of Local Anesthetics

Commonly used local anesthetics are listed in Table 121. These drugs share a common chemical strategy consisting of both a lipophilic and hydrophilic group connected by an intermediate chain (Fig. 121). A local anesthetic is chosen depending on factors such as: (1) the operative site and nature of the procedure; (2) the type of regional anesthesia desired (such as single peripheral nerve block or spinal anesthesia); (3) the patients size and general health; and (4) the duration of action of the anesthetic.3 The caine suffix (lidocaine, procaine, and so on) usually identifies local anesthetics.. The first clinically useful local anesthetic identified was cocaine in


SECTION 2 Pharmacology of the Central Nervous System

Lipophilic Group Intermediate Chain


C2H5 C2H5
Hydrophilic Group

FIGURE 121 Structure of lidocaine. The basic structure of a lipophilic and hydrophilic group connected by an intermediate chain is common to most local anesthetics.

thetics can cause toxic side effects when sufficient amounts reach the systemic circulation (see Systemic Effects of Local Anesthetics, later). This occurrence is usually not a problem in most single, small doses of regional anesthesia, but the build-up of the drug in the bloodstream should be monitored if these drugs are administered repeatedly or continuously to treat chronic pain.51,59 Local anesthetics are usually eliminated by hydrolyzing or breaking apart the drug molecule. This metabolic hydrolysis is catalyzed by hepatic enzymes or enzymes circulating in the plasma (e.g., the plasma cholinesterase). Once metabolized, the kidneys excrete the polar drug metabolites.

Clinical Use of Local Anesthetics

The primary clinical uses of local anesthetics according to their method of administration and specific indications are presented here. 1. Topical administration. Local anesthetics can be applied directly to the surface of the skin, mucous membranes, cornea, and other regions to produce analgesia. This is usually done for the symptomatic relief of minor surface irritation and injury (minor burns, abrasions, inflammation). Local anesthetics can also be applied topically to reduce pain prior to minor surgical procedures such as wound cleansing, myringotomy, circumcision, and cataract surgery.7,52,57 A topical anesthesia can be made by applying a single agent or a mixture of two or more local anesthetics (e.g., lidocaine and prilocaine).4,49,52 Topical anesthesia has also been used to improve motor function in some patients with skeletal muscle hypertonicity resulting from a cerebrovascular accident (CVA) or head trauma.53 In this situation, a local anesthetic (e.g., 20% benzocaine) can be sprayed on the skin overlying hypertonic muscles, and then various exercises and facilitation techniques can be performed to increase and improve mobility in the affected limbs. The rationale of this treatment is that it temporarily decreases abnormal or excessive excitatory feedback of cutaneous receptors on efferent motor pathways so that normal integration and control of motor function can be reestablished. Preliminary evidence has suggested that repeated application of this

1884. However, its tendency for abuse and its high incidence of addiction and systemic toxicity initiated the search for safer local anesthetics such as those in Table 121. One should note that cocaine abuse grew because of its effects on the brain, not for its local anesthetic effects. Cocaine produces intense feelings of euphoria and excitement through increased synaptic transmission in the brain. This fact explains why cocaine abusers inject or apply this drug to the nasal mucous membranes (i.e., snorting, so that it absorbs through those membranes and into systemic circulation where it ultimately reaches the brain).

Local anesthetics are administered through a variety of routes and techniques depending on the specific clinical situation (see Clinical Use of Local Anesthetics, below). In local anesthesia, the drug should remain at the site of administration. For instance, injecting procaine (Novocain) into the trigeminal nerve area during a dental procedure will be more effective if it is not washed away from the administration site by blood flow through that region. Likewise, injection of a local anesthetic into the area surrounding the spinal cord (e.g., epidural or spinal injection, see next section) will be more effective if the drug remains near the administration site.31,32 Consequently, a vasoconstricting agent (e.g., epinephrine) is often administered simultaneously to help prevent washout from the desired site.42,46 Preventing the anesthetic from reaching the bloodstream is also beneficial because local anes-

Chapter 12 Local Anesthetics


Table 121
Generic Name Articane Benzocaine Bupivacaine


Trade Name(s) Septocaine Americaine, others Marcaine, Sensorcaine Onset of Action Rapid Slow to Intermediate Duration of Action Intermediate Long Principle Use(s) Peripheral nerve block Topical Infiltration; Peripheral nerve block; Epidural; Spinal; Sympathetic block Topical Infiltration; Peripheral nerve block; Epidural; Intravenous regional block Topical Infiltration; Peripheral nerve block; Epidural Infiltration; Peripheral nerve block; Epidural Infiltration; Peripheral Nerve Block; Epidural; Spinal; Transdermal; Topical; Sympathetic block; Intravenous regional block Infiltration; Peripheral nerve block; Epidural; Intravenous regional block Topical Infiltration; Peripheral nerve block
(Continued on following page)

Butamben Chloroprocaine

Butesin Picrate Nesacaine



Dibucaine Etidocaine

Nupercainal Duranest





Slow to Intermediate

Short to Long






Carbocaine, Polocaine

Intermediate to Rapid


Pramoxine Prilocaine

Prax, Tronolane Citanest




SECTION 2 Pharmacology of the Central Nervous System

Table 121
Generic Name Procaine


Trade Name(s) Novocain Onset of Action* Intermediate Duration of Action* Short Principle Use(s) Infiltration; Peripheral nerve block; Spinal Topical; Spinal




Intermediate to Long

*Values for onset and duration of action refer to use during injection. Relative durations of action are as follows: short 3060 min; intermediate 13 hr; and long 310 hr of action. Source: USP DI, 25th Edition. Copyright 2005. Thomson MICROMEDEX. Permission granted.

technique may produce long-lasting improvements in joint mobility and gait characteristics in patients with hypertonicity caused by various central nervous system (CNS) disorders.53 2. Transdermal administration. The drug is applied to the surface of the skin or other tissues with the intent that the drug will absorb into underlying tissues. Transdermal administration of some local anesthetics may be enhanced by the use of electrical current (iontophoresis) or ultrasound (phonophoresis; see Appendix A).18,50,66 Moreover, iontophoresis and phonophoresis offer the advantage of anesthetizing a region of the skin before treating painful subcutaneous structures (bursae, tendons, other soft tissues) without breaking the skin. Physical therapists can therefore use iontophoresis and phonophoresis to administer local anesthetics, such as lidocaine, for treating certain musculoskeletal injuries. However, a comprehensive discussion of the efficacy of these techniques in physical therapy practice is beyond the scope of this chapter. Readers are directed to several references at the end of this chapter that address this topic in more detail.12,18,20 Administration of local anesthetics via iontophoresis can also be used to produce topical anesthesia prior to certain dermatologic procedures. For example, lidocaine iontophoresis can adequately anesthetize a small patch of skin for performing a minor surgical procedure (placement of an intravenous catheter, laser treatment of port-wine stains, and so forth).18,50,66 Iontophoretic application of local anesthetics offers

a noninvasive alternative to subcutaneous injection of these drugs, and use of iontophoresis seems to be gaining popularity as a method for producing local anesthesia before specific dermatologic surgeries.29 Finally, local anesthetics can be administered via a transdermal patch.1 In particular, transdermal patches containing 5% lidocaine have been used to treat localized pain in musculoskeletal conditions (osteoarthritis, low back pain, myofascial pain)22,25,26 and various types of neuropathic pain (postherpetic neuralgia, diabetic neuropathy).2,24,58 As indicated in Chapter 2, transdermal patches provide a convenient and predictable method for administering drugs to a given anatomical site, and lidocaine patches are now being used to provide symptomatic relief in many conditions involving fairly localized pain. 3. Infiltration anesthesia. The drug is injected directly into the selected tissue, allowing it to diffuse to sensory nerve endings within that tissue. This technique saturates an area such as a skin laceration for performing surgical repair (suturing). 4. Peripheral nerve block. The anesthetic is injected close to the nerve trunk so that transmission along the peripheral nerve is interrupted.61 This type of local anesthesia is common in dental procedures (restorations, tooth extractions, and so on) and can also be used to block other peripheral nerves to allow certain surgical procedures of the hand, foot, shoulder, and so forth. 11,56,65 Injection near larger nerves (femoral, sciatic) or around a nerve plexus (brachial plexus)

Chapter 12 Local Anesthetics


can also be used to anesthetize larger areas of an upper or lower extremity.23,37,39 Nerve blocks can be classified as minor when only one distinct nerve (e.g., ulnar, median) is blocked, or major, when several peripheral nerves or a nerve plexus (brachial, lumbosacral) is involved. Nerve blocks can also be continued after the completion of the surgery to provide optimal pain management.28,55 In this situation, a small catheter is left implanted near the nerve(s) so that small dosages of the local anesthetic are administered for the first 24 hours or so after surgery. Continuous peripheral nerve blocks have therefore been used to control postsurgical pain in several clinical situations, and these techniques should continue to gain acceptance as technical improvements are made in this form of drug delivery.39,55 Prolonged administration of local anesthetics within skeletal muscle, however, can produce localized muscle pain and necrosis.67,68 Hence, therapists should be aware of this possibility if patients report muscle pain and weakness following the use of continuous peripheral nerve blocks. 5. Central neural blockade. The anesthetic is injected within the spaces surrounding the spinal cord10 (Fig.122). Specifically, the term epidural nerve blockade refers to injection of the drug into the epidural spacethat is, the space between the bony vertebral column and the dura mater. A variation of epidural administration known as a caudal block is sometimes performed by injecting the local anesthetic into the lumbar epidural space via the sacral hiatus (see Fig. 122). Spinal nerve blockade refers to injection within the subarachnoid space that is, the space between the arachnoid membrane and the pia mater. Spinal blockade is also referred to as intrathecal anesthesia because the drug is injected within the tissue sheaths surrounding the spinal cord (intrathecal means within a sheath; see Chapter 2). In theory, epidural and spinal blocks can be done at any level of the cord, but they are usually administered at the L3-4 or L4-5 vertebral interspace (i.e., caudal to the L-2 vertebral body, which is the point where the spinal cord ends). Epidural anesthesia is somewhat easier to perform than spinal blockade because the epidural space is larger and more accessible than the subarachnoid space. However, spinal anesthesia is



Epidural or peridural nerve block




Spinal nerve block

L5 S1 S2 S3 S4 S5

Caudal block

Coccygeal nerve

FIGURE 122 Sites of epidural and spinal administration of a local anesthetic. Caudal block represents epidural administration via the sacral hiatus. (From Clark JB, Queener SF, Karb VB. Pharmacological Basis of Nursing Practice. 4th ed. St Louis: CV Mosby; 1993: 688. Reproduced with permission.)

more rapid and usually creates a more effective or solid block using a smaller amount of the local anesthetic.10,44 The drawback, of course, is that higher concentrations of the drug are administered in close proximity to neural structures during spinal anesthesia. Local anesthetics are neurotoxic when administered in high concentrations.62,63 Spinal anesthesia therefore carries a somewhat higher risk for neurotoxicity because a relatively large amount of the local anesthetic is being introduced fairly close to the spinal cord and related neural structures (cauda equina). Any physical damage from the injection technique or neurotoxicity from the drugs will


SECTION 2 Pharmacology of the Central Nervous System

therefore be more problematic during spinal administration compared to the epidural route. Central neural blockade is used whenever analgesia is needed in a large region, and epidural and spinal routes are used frequently to administer local anesthetics during obstetric procedures (including caesarean delivery).30,44 These routes can also be used as an alternative to general anesthesia for other surgical procedures including lumbar spine surgery and hip and knee arthroplasty.23,45 The epidural and intrathecal routes have also been used to administer anesthetics and narcotic analgesics for relief of acute and chronic pain.6,19 In these instances, an indwelling catheter is often left implanted in the epidural or subarachnoid space to allow repeated or continuous delivery of the anesthetic to the patient. The use of implanted drug delivery systems in managing chronic and severe pain is discussed further in Chapters 14 and 17. 6. Sympathetic block. Although blockade of sympathetic function usually occurs during peripheral and central nerve blocks, sometimes the selective interruption of sympathetic efferent discharge is desirable. This intervention is especially useful in cases of complex regional pain syndrome (CRPS). This syndrome, also known as reflex sympathetic dystrophy syndrome (RSDS) and causalgia, involves increased sympathetic discharge to an upper or lower extremity, often causing severe pain and dysfunction in the distal part of the extremity. As part of the treatment, a local anesthetic can be administered to interrupt sympathetic discharge to the affected extremity.33,64 One approach is to inject the local anesthetic into the area surrounding the sympathetic chain ganglion that innervates the affected limb. For example, injection near the stellate ganglion is performed when the upper extremity is involved, and injections around the sympathetic ganglion at the L2 vertebral level are used for lower-extremity CRPS.33 Usually a series of five injections on alternate days is necessary to attenuate the sympathetic discharge and to provide remission from the CRPS episode. Alternatively, the local anesthetic can be administered subcutaneously to an affected area,38 or injected intravenously into the affected limb using regional intravenous block techniques (see next section).35 Hence, several techniques are currently being

used to promote sympathetic blockade using local anesthetic drugs. With these techniques, the goal is not to provide analgesia, but rather to impair efferent sympathetic outflow to the affected extremity. 7. Intravenous Regional Anesthesia (Bier block). During intravenous regional anesthesia (also known as Bier block), the anesthetic is injected into a peripheral vein located in a selected limb (arm or leg).9 The local vasculature can then carry the anesthetic to the nerves in that extremity, thereby producing anesthesia in the limb. A tourniquet is also applied proximally on the limb to localize the drug temporarily within the extremity, and to prevent the anesthetic from reaching the systemic circulation where it would cause toxic effects on the heart and CNS. This technique is somewhat difficult to use because the tourniquet can cause pain or increase the risk of ischemic neuropathy if left in place for more than 2 hours.48 Intravenous regional block, however, can be used to anesthetize the forearmhand or distal leg-ankle-foot for short periods to allow certain surgical procedures or to treat conditions such as CRPS.34,35

Mechanism of Action
Local anesthetics work by blocking action potential propagation along neuronal axons, which is believed to occur from the anesthetic molecule inhibiting the opening of membrane sodium channels.44,60 The sudden influx of sodium into the neuron through open (activated) ion channels depolarizes the neuron during impulse propagation. If the sodium ion channels are inhibited from opening along a portion of the axon, the action potential will not be propagated past that point. If the neuron is sensory in nature, this information will not reach the brain and will result in anesthesia of the area innervated by that neuron. Exactly how local anesthetics inhibit the sodium channel from opening has been the subject of much debate. Although several theories exist, the current consensus is that local anesthetics temporarily attach to a binding site or receptor located on or within the sodium channel.16,36,60 These receptors probably control the opening of the channel, and when bound by the anesthetic molecule, the sodium channel is maintained in a closed, inactivated position. Several sites have been proposed to explain exactly where the local

Chapter 12 Local Anesthetics

Na+ Channel (open/ no anesthetic)
Na + +


+ Na Channel (closed/ blocked by anesthetic)


+ Na

local anesthetic FIGURE 123 Schematic diagram showing mechanism of action of local anesthetics on the nerve membrane. Local anesthetics appear to bind directly to a site within the sodium channel, thereby locking the channel in a closed position, thus preventing sodium entry and action potential propagation.

anesthetic binds on the sodium channel protein (Fig. 123).36,43,60 The most likely binding site is within the lumen or pore of the channel itself, possibly at the inner, cytoplasmic opening of the channel.16,60 When bound by the anesthetic molecule, this site may effectively lock the sodium channel shut (much in the same way that the appropriate key fitting into a door keyhole is able to lock a door). Consequently, local anesthetics appear to bind directly to sodium channels on the nerve axon. By keeping these channels in a closed, inactivated state, the anesthetic prevents action potential propogation along the affected portion of the axon. Likewise, only a relatively short portion of the axon (e.g., the length of 3 nodes of Ranvier in a myelinated neuron) needs to be affected by the anesthetic to block action potential propogation.62 That is, the anesthetic does not need to affect the entire length of the axon, but block only one specific segment of the axon to completely prevent sensory or motor information from being transmitted past the point of the blockade.

Differential Nerve Block

Differential nerve block refers to the ability of a given local anesthetic dose to block specific nerve fiber groups depending on the size (diameter) of the fibers.54, 62 In general, smaller diameter fibers seem to be the most sensitive to anesthetic effects, with progressively larger fibers being affected as anesthetic concentration increases.62 This point is significant because different diameter fibers transmit different types of information (Table 122). Thus, information transmitted by the smallest fibers will be lost first, with other types of transmission being successively lost as the local anesthetic effect increases. The smallest diameter (type C) fibers that transmit pain are usually

the first sensory information blocked as the anesthetic takes effect. Type C fibers also transmit postganglionic autonomic information, including sympathetic vasomotor control of the peripheral vasculature, and are most susceptible to block by local anesthetics. Other sensory informationsuch as temperature, touch, and proprioceptionis successively lost as the concentration and effect of the anesthetic increases. Finally, skeletal motor function is usually last to disappear because efferent impulses to the skeletal muscle are transmitted over the large type A-alpha fibers. The exact reason for the differential susceptibility of nerve fibers based on their axonal diameter is not known. One possible explanation is that the anesthetic is able to affect a critical length of the axon more quickly in unmyelinated fibers, or small myelinated neurons with nodes of Ranvier that are spaced closely together compared to larger fibers where the nodes are farther apart.17 As indicated earlier, a specific length of the axon must be affected by the anesthetic so that action potentials cannot be transmitted past the point of blockade. Other factors such as the firing rate of each axon or the position of the axon in the nerve bundle (e.g., in the outer part of the bundle versus buried toward the center of the nerve) may also affect susceptibility to local anesthesia.62 In any event, from a clinical perspective the smaller-diameter fibers appear to be affected first, although the exact reasons for this phenomenon remain to be determined. The clinical importance of a differential nerve block is that certain sensory modalities may be blocked without the loss of motor function. Fortuitously, the most susceptible modality is pain because analgesia is usually the desired effect. If the dosage and administration of the anesthetic is optimal, it will produce analgesia without any significant loss of skeletal muscle function. This fact may be advantageous if motor function is required, such as during labor and delivery.14 If


SECTION 2 Pharmacology of the Central Nervous System

Table 122
Fiber Type* Type A Alpha


Function Proprioception, motor Touch, pressure Muscle spindles Pain, temperature Preganglionic, autonomic Diameter ( m) 1220 Myelination Heavy Conduction Velocity (m/s) 70120 Sensitivity to Block

Beta Gamma Delta Type B

512 36 25 3

Heavy Heavy Heavy Light

3070 1530 1230 315

Type C Dorsal Root Sympathetic Pain Postganglionic 0.41.2 0.31.3 None None 0.52.3 0.72.3

*Fiber types are classified according to the system established by Gasser and Erlanger. Am J Physiol. 1929; 88:581. Reproduced with permission from Katzung BG. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw Hill; 2004.

local anesthetics are used to produce sympathetic blockade, postganglionic type C fibers are the first to be blocked, thus producing the desired effect at the lowest anesthetic concentration.

Systemic Effects of Local Anesthetics

The intent of administering a local anesthetic is to produce a regional effect on specific neurons. However, these drugs may occasionally be absorbed into the general circulation and exert various effects on other organs and tissues. Because local anesthetics inhibit action potential initiation and propogation, the most important systemic effects involve the CNS and cardiovascular system.8,21,27 That is, local anesthetics can inadvertently disrupt the excitability of the CNS and cardiac tissues if meaningful amounts of these drugs reach the systemic circulation. Regarding CNS effects, virtually all local anesthetics stimulate the brain initially, and symptoms such as somnolence, confusion, agitation, excitation, and

seizures can occur if sufficient amounts reach the brain via the bloodstream.8,17 Central excitation is usually followed by a period of CNS depression. This depression may result in impaired respiratory function, and death may occur due to respiratory depression.17 The primary cardiovascular effects associated with local anesthetics include decreased cardiac excitation, heart rate, and force of contraction.5,17 Again, this general inhibitory effect on the myocardium may produce serious consequences if sufficient amounts of the local anesthetic reach the general circulation.17 Systemic effects are more likely to occur with long-acting anesthetics if an excessive dose is used, if absorption into the blood stream is accelerated for some reason, or if the drug is accidentally injected into the systemic circulation rather than into extravascular tissues.17,40 Other factors that can predispose a patient to systemic effects include the type of local anesthetic administered, as well as the route and method of administration.3 Therapists and other health care professionals should always be alert for signs of the systemic effects of local anesthetics in patients. Early symptoms of CNS toxicity include ringing/buzzing

Chapter 12 Local Anesthetics


in the ears (tinnitus), agitation, restlessness, and decreased cutaneous sensation around the mouth or other areas of the skin.59 Changes in heart rate (bradycardia), electrocardiogram (ECG) abnormalities, or clinical signs of cardiac depression (fatigue, dizziness) may indicate cardiotoxicity. Again, early recognition of these CNS and cardiac abnormalities is essential to help avert fatalities due to the drugs systemic effects.

Significance in Rehabilitation
Physical therapists may encounter the use of local anesthetics in several patient situations because of their various clinical applications. For example, therapists may be directly involved in the topical or transdermal administration of local anesthetics. As discussed earlier, repeated topical application of local anesthetics may help produce long-term improvements in motor function in patients with skeletal muscle hypertonicity, so therapists may want to consider incorporating topical anesthetics into the treatment of certain patients with CNS dysfunction. Therapists may also administer local anesthetics transdermally, using the techniques of iontophoresis and phonophoresis. Agents such as lidocaine can be administered through this method for the treatment of acute inflammation in bursitis, tendinitis, and so on. Therapists may also be working with patients who are receiving local anesthetic injections for the treatment of CRPS/RSDS. Since these patients often receive a series of anesthetic injections, therapists may want to schedule the rehabilitation session immediate-

ly after each injection so that they can perform exercises and other rehabilitation techniques while the anesthetic is still in effect. This strategy may help reestablish normal sympathetic function and blood flow to the affected extremity so that optimal results are obtained from the sympathetic blockade. Finally, therapists may work with patients who are receiving central neural blockade in the form of an epidural or spinal injection. These procedures are common during natural and caesarean childbirth and in some other surgical procedures. Administration of local anesthetics into the spaces around the spinal cord are also used to treat individuals with severe and chronic painthat is, patients recovering from extensive surgery, patients who have cancer, or patients with other types of intractable pain. In these situations, therapists may notice that an indwelling catheter has been placed in the patients epidural or subarachnoid space to allow repeated or sustained administration of the spinal anesthesia. In situations where central neural blockade is used, therapists should be especially aware that sensation might be diminished below the level of epidural or spinal administration. Decreased sensation to thermal agents and electrical stimulation will occur when the central block is in effect.10 Likewise, motor function may be affected in the lower extremities when local anesthetics are administered spinally or epidurally.10 Hence, therapists should test sensation and motor strength before applying any physical agents or attempting ambulation with patients who have received some type of central neural blockade using a local anesthetic.

Local Anesthetics
Brief History. R.D. is a 35-year-old man who developed pain in his right shoulder after spending the weekend chopping firewood. He was examined by a physical therapist and evaluated as having supraspinatus tendinitis. Apparently, this tendinitis recurred intermittently, usually after extensive use of the right shoulder. During past episodes, the tendinitis was resistant to treatment and usually took several months to resolve. Decision/Solution. The therapist began an aggressive rehabilitation program consisting of daily heat, ultrasound, soft-tissue massage, and exercise. Soft-tissue massage consisted of transverse-friction techniques applied to the supraspinatus tendon. In order to improve the patients tolerance to this technique, 5 percent lidocaine (Xylocaine) solution was administered via iontophoresis prior to the transverse-friction massage. This approach allowed R.D. and the therapist to perform both the massage technique and subsequent exercises more aggressively. Under this regimen, the supraspinatus tendinitis was resolved and the patient had full, pain-free use of the right shoulder within 3 weeks.


SECTION 2 Pharmacology of the Central Nervous System

Local anesthetics are used frequently when a limited, well-defined area of anesthesia is required, as is the case for most minor surgical procedures. Depending on the method of administration, local anesthetics can be used to temporarily block transmission in the area of peripheral nerve endings, along the trunk of a single peripheral nerve, along several peripheral nerves or plexuses, or at the level of the

spinal cord. Local anesthetics may also be used to block efferent sympathetic activity. These drugs appear to block transmission along nerve axons by binding to membrane sodium channels and by preventing the channels from opening during neuronal excitation. Physical therapists may frequently encounter the use of these agents in their patients for both short-term and long-term control of pain, as well as in the management of sympathetic hyperactivity.

1. Argoff CE, Galer BS, Jensen MP, et al. Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states: assessment with the Neuropathic Pain Scale. Curr Med Res Opin. 2004;20(suppl 2): S21S28. 2. Barbano RL, Herrmann DN, Hart-Gouleau S, et al. Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy. Arch Neurol. 2004;61:914918. 3. Berde CB, Strichartz GR. Local anesthetics. In: Miller RD, ed. Anesthesia. Volume 1. 5th ed. Philadelphia: Churchill Livingstone; 2000. 4. Bloch Y, Levkovitz Y, Atshuler A, et al. Use of topical application of lidocaine-prilocaine cream to reduce injection-site pain of depot antipsychotics. Psychiatr Serv. 2004;55:940941. 5. Borgeat A, Ekatodramis G, Blumenthal S. Interscalene brachial plexus anesthesia with ropivacaine 5 mg/mL and bupivacaine 5 mg/mL: effects on electrocardiogram. Reg Anesth Pain Med. 2004;29:557563. 6. Bourne MH. Analgesics for orthopedic postoperative pain. Am J Orthop. 2004;33:128135. 7. Brady-Fryer B, Wiebe N, Lander JA. Pain relief for neonatal circumcision. Cochrane Database Syst Rev. 2004;CD004217. 8. Breslin DS, Martin G, Macleod DB, et al. Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: a report of two cases. Reg Anesth Pain Med. 2003;28:144147. 9. Brill S, Middleton W, Brill G, Fisher A. Biers block: 100 years old and still going strong! Acta Anaesthesiol Scand. 2004;48:117122. 10. Brown DL. Spinal, epidural, and caudal anesthesia. In: Miller RD, ed. Anesthesia. Volume 1 5th ed. Philadelphia: Churchill Livingstone; 2000. 11. Budenz AW. Local anesthetics in dentistry: then and now. J Calif Dent Assoc. 2003;31:388396. 12. Byl NN. The use of ultrasound as an enhancer for transcutaneous drug delivery: phonophoresis. Phys Ther. 1995;75:539553. 13. Capdevila X, Dadure C. Perioperative management for one day hospital admission: regional anesthesia is better than general anesthesia. Acta Anaesthesiol Belg. 2004;(suppl 55):3336.

14. Capogna G, Camorcia M. Epidural analgesia for childbirth: effects of newer techniques on neonatal outcome. Paediatr Drugs. 2004;6:375386. 15. Casati A, Cappelleri G, Aldegheri G, et al. Total intravenous anesthesia, spinal anesthesia or combined sciatic-femoral nerve block for outpatient knee arthroscopy. Minerva Anestesiol. 2004;70:493502. 16. Catterall WA. Molecular mechanisms of gating and drug block of sodium channels. Novartis Found Symp. 2002;241:206218. 17. Catterall WA, Mackie K. Local anesthetics. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 18. Ciccone CD. Iontophoresis. In: Robinson AJ, SnyderMackler L, eds. Clinical Electrophysiology. 3rd ed. Baltimore: Williams and Wilkins; In press. 19. Colwell CW, Jr. The use of the pain pump and patient-controlled analgesia in joint reconstruction. Am J Orthop. 2004;33(suppl 5):1012. 20. Costello CT, Jeske AH. Iontophoresis: applications in transdermal medication delivery. Phys Ther. 1995;75: 554563. 21. Crews JC, Rothman TE. Seizure after levobupivacaine for interscalene brachial plexus block. Anesth Analg. 2003;96:11881190. 22. Dalpiaz AS, Lordon SP, Lipman AG. Topical lidocaine patch therapy for myofascial pain. J Pain Palliat Care Pharmacother. 2004;18:1534. 23. Davies AF, Segar EP, Murdoch J, et al. Epidural infusion or combined femoral and sciatic nerve blocks as perioperative analgesia for knee arthroplasty. Br J Anaesth. 2004;93:368374. 24. Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia. Drugs. 2004;64:937947. 25. Galer BS, Gammaitoni AR, Oleka N, et al. Use of the lidocaine patch 5% in reducing intensity of various pain qualities reported by patients with low-back pain. Curr Med Res Opin. 2004;20(suppl 2): S5S12. 26. Gammaitoni AR, Galer BS, Onawola R, et al. Lidocaine patch 5% and its positive impact on pain qualities in osteoarthritis: results of a pilot 2-week, open-label study using the Neuropathic Pain Scale. Curr Med Res Opin. 2004;20(suppl 2):S13S19.

Chapter 12 Local Anesthetics 27. Graf BM. The cardiotoxicity of local anesthetics: the place of ropivacaine. Curr Top Med Chem. 2001; 1:207214. 28. Grant SA, Nielsen KC, Greengrass RA, et al. Continuous peripheral nerve block for ambulatory surgery. Reg Anesth Pain Med. 2001;26:209214. 29. Greenbaum SS. Iontophoresis as a tool for anesthesia in dermatologic surgery: an overview. Dermatol Surg. 2001;27:10271030. 30. Gogarten W. Spinal anaesthesia for obstetrics. Best Pract Res Clin Anaesthesiol. 2003;17:377392. 31. Hocking G, Wildsmith JA. Intrathecal drug spread. Br J Anaesth. 2004;93:568578. 32. Inoue S, Kawaraguchi Y, Kitaguchi K, Furuya H. Inclusion of epinephrine to hyperbaric tetracaine and the supine position enhance the cephalad spread of spinal anaesthesia compared with hyperbaric tetracaine alone in the lithotomy position. Acta Anaesthesiol Scand. 2004;48:342346. 33. Karakurum G, Pirbudak L, Oner U, et al. Sympathetic blockade and amitriptyline in the treatment of reflex sympathetic dystrophy. Int J Clin Pract. 2003;57: 585587. 34. Karalezli N, Karalezli K, Iltar S, et al. Results of intravenous regional anaesthesia with distal forearm application. Acta Orthop Belg. 2004;70:401405. 35. Lake AP. Intravenous regional sympathetic block: past, present and future? Pain Res Manag. 2004;9:3537. 36. Leuwer M, Haeseler G, Hecker H, et al. An improved model for the binding of lidocaine and structurally related local anaesthetics to fast-inactivated voltageoperated sodium channels, showing evidence of cooperativity. Br J Pharmacol. 2004;141:4754. 37. Liisanantti O, Luukkonen J, Rosenberg PH. Highdose bupivacaine, levobupivacaine and ropivacaine in axillary brachial plexus block. Acta Anaesthesiol Scand. 2004;48:601606. 38. Linchitz RM, Raheb JC. Subcutaneous infusion of lidocaine provides effective pain relief for CRPS patients. Clin J Pain. 1999;15:6772. 39. Long TR, Wass CT, Burkle CM. Perioperative interscalene blockade: an overview of its history and current clinical use. J Clin Anesth. 2002;14:546556. 40. Mather LE, Chang DH. Cardiotoxicity with modern local anaesthetics: is there a safer choice? Drugs. 2001; 61:333342. 41. Mattingly JE, DAlessio J, Ramanathan J. Effects of obstetric analgesics and anesthetics on the neonate: a review. Paediatr Drugs. 2003;5:615627. 42. Naftalin LW, Yagiela JA. Vasoconstrictors: indications and precautions. Dent Clin North Am. 2002;46: 733746. 43. Nau C, Wang GK. Interactions of local anesthetics with voltage-gated Na channels. J Membr Biol. 2004; 201:18. 44. Ng K, Parsons J, Cyna AM, Middleton P. Spinal versus epidural anaesthesia for caesarean section. Cochrane Database Syst Rev. 2004;CD003765. 45. Parker MJ, Handoll HH, Griffiths R. Anaesthesia for hip fracture surgery in adults. Cochrane Database Syst Rev. 2004;CD000521.


46. Pitkanen M, Rosenberg PH. Local anaesthetics and additives for spinal anaesthesiacharacteristics and factors influencing the spread and duration of the block. Best Pract Res Clin Anaesthesiol. 2003;17: 305322. 47. Portnoy D, Vadhera RB. Mechanisms and management of an incomplete epidural block for cesarean section. Anesthesiol Clin North America. 2003;21:3957. 48. Rodola F, Vagnoni S, Ingletti S. An update on Intravenous Regional Anaesthesia of the arm. Eur Rev Med Pharmacol Sci. 2003;7:131138. 49. Rogers TL, Ostrow CL. The use of EMLA cream to decrease venipuncture pain in children. J Pediatr Nurs. 2004;19:3339. 50. Rose JB, Galinkin JL, Jantzen EC, Chiavacci RM. A study of lidocaine iontophoresis for pediatric venipuncture. Anesth Analg. 2002;94:867871. 51. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med. 2004; 29:564575. 52. Rosenthal D, Murphy F, Gottschalk R, et al. Using a topical anaesthetic cream to reduce pain during sharp debridement of chronic leg ulcers. J Wound Care. 2001;10:503505. 53. Sabbahi MA, De Luca CJ: Topical anesthetic-induced improvements in the mobility of patients with muscular hypertonicity: preliminary results. J Electromyogr Kinesiol. 1991;1:4146. 54. Sakai T, Tomiyasu S, Yamada H, et al. Quantitative and selective evaluation of differential sensory nerve block after transdermal lidocaine. Anesth Analg. 2004; 98:248251. 55. Shinaman RC, Mackey S. Continuous peripheral nerve blocks. Curr Pain Headache Rep. 2005;9:2429. 56. Singelyn FJ, Lhotel L, Fabre B. Pain relief after arthroscopic shoulder surgery: a comparison of intraarticular analgesia, suprascapular nerve block, and interscalene brachial plexus block. Anesth Analg. 2004; 99:589592. 57. Soliman MM, Macky TA, Samir MK. Comparative clinical trial of topical anesthetic agents in cataract surgery: lidocaine 2% gel, bupivacaine 0.5% drops, and benoxinate 0.4% drops. J Cataract Refract Surg. 2004; 30:17161720. 58. Stacey BR. Management of peripheral neuropathic pain. Am J Phys Med Rehabil. 2005;84(suppl):S4S16. 59. Stewart J, Kellett N, Castro D. The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. Anesth Analg. 2003;97:412416. 60. Tsang SY, Tsushima RG, Tomaselli GF, et al. A multifunctional aromatic residue in the external pore vestibule of Na channels contributes to the local anesthetic receptor. Mol Pharmacol. 2005;67:424434. 61. Wedel DJ. Nerve blocks. In: Miller RD, ed. Anesthesia. Volume 1. 5th ed. Philadelphia: Churchill Livingstone; 2000. 62. White PF, Katzung BG. Local anesthetics. In: Katzung BG, ed. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw-Hill; 2004.


SECTION 2 Pharmacology of the Central Nervous System 66. Zempsky WT, Sullivan J, Paulson DM, Hoath SB. Evaluation of a low-dose lidocaine iontophoresis system for topical anesthesia in adults and children: a randomized, controlled trial. Clin Ther. 2004;26: 11101119. 67. Zink W, Graf BM. Local anesthetic myotoxicity. Reg Anesth Pain Med. 2004;29:333340. 68. Zink W, Seif C, Bohl JR, et al. The acute myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blockades. Anesth Analg. 2003; 97:11731179.

63. Yamashita A, Matsumoto M, Matsumoto S, et al. A comparison of the neurotoxic effects on the spinal cord of tetracaine, lidocaine, bupivacaine, and ropivacaine administered intrathecally in rabbits. Anesth Analg. 2003;97:512519. 64. Yung Chung O, Bruehl SP. Complex Regional Pain Syndrome. Curr Treat Options Neurol. 2003;5:499511. 65. Zaric D, Boysen K, Christiansen J, Haastrup U, Kofoed H, Rawal N. Continuous popliteal sciatic nerve block for outpatient foot surgerya randomized, controlled trial. Acta Anaesthesiol Scand. 2004;48:337341.


Drugs Affecting Skeletal Muscle

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Skeletal Muscle Relaxants

Skeletal muscle relaxants are used to treat conditions associated with hyperexcitable skeletal muscle specifically, spasticity and muscle spasms. Although these two terms are often used interchangeably, spasticity and muscle spasms represent two distinct abnormalities. The use of relaxant drugs, however, is similar in each condition because the ultimate goal is to normalize muscle excitability without a profound decrease in muscle function. Considering the number of rehabilitation patients with muscle hyperexcitability that is associated with either spasm or spasticity, skeletal muscle relaxants represent an important class of drugs to the rehabilitation specialist. Drugs discussed in this chapter are used to decrease muscle excitability and contraction via an effect at the spinal cord level, at the neuromuscular junction, or within the muscle cell itself. Some texts also classify neuromuscular junction blockers such as curare and succinylcholine as skeletal muscle relaxants. However, these drugs are more appropriately classified as skeletal muscle paralytics because they eliminate muscle contraction by blocking transmission at the myoneural synapse. This type of skeletal muscle paralysis is used primarily during general anesthesia; using neuromuscular blockers as an adjunct in surgery was discussed in Chapter 11. Skeletal muscle relaxants do not typically prevent muscle contraction; they only attempt to normalize muscle excitability to decrease pain and improve motor function. be used to describe two different types of increased excitability, which result from different underlying pathologies. Spasticity occurs in many patients following an injury to the central nervous system (CNS), including cord-related problems (multiple sclerosis, spinal cord transection) and injuries to the brain (CVA, cerebral palsy, acquired brain injury). Although there is considerable controversy about the exact changes in motor control, most clinicians agree that spasticity is characterized primarily by an exaggerated muscle stretch reflex (Fig. 131).40,52,79 This abnormal reflex activity is velocity-dependent, with a rapid lengthening of the muscle invoking a strong contraction in the

CNS Higher Centers

control/inhibition Spinal Cord Ia afferent

motor neuron motor neuron

muscle spindle

Skeletal Muscle

Increased Muscle Tone: Spasticity Versus Muscle Spasms

Much confusion and consternation often arise from the erroneous use of the terms spasticity and spasm. For the purpose of this text, these terms will

FIGURE 131 Schematic illustration of the basic components of the stretch reflex. Normally, higher CNS centers control the sensitivity of this reflex by inhibiting synaptic connections within the spinal cord. Spasticity is thought to occur when this higher center influence is lost because of cerebral trauma or damage to descending pathways in the spinal cord.



SECTION 3 Drugs Affecting Skeletal Muscle

stretched muscle. The neurophysiologic mechanisms underlying spasticity are complex, but this phenomenon occurs when supraspinal inhibition or control is lost because of a lesion in the spinal cord or brain.40,52,54 Presumably, specific upper motor neuron lesions interrupt the cortical control of stretch reflex and alpha motor neuron excitability. Spasticity, therefore, is not in itself a disease but rather the motor sequela to pathologies such as cerebral vascular accident (CVA), cerebral palsy, multiple sclerosis (MS), and traumatic lesions to the brain and spinal cord (including quadriplegia and paraplegia). Skeletal muscle spasms are used to describe the increased tension often seen in skeletal muscle after certain musculoskeletal injuries and inflammation (muscle strains, nerve root impingements, etc.) occur.20,96 This tension is involuntary, so the patient is unable to relax the muscle. Spasms differ from spasticity because spasms typically arise from an orthopedic injury to a musculoskeletal structure or peripheral nerve root rather than an injury to the CNS. Likewise, muscle spasms are often a continuous, tonic contraction of specific muscles rather than the velocitydependent increase in stretch reflex activity commonly associated with spasticity. The exact reasons for muscle spasms are poorly understood. According to some authorities, muscle spasms occur because a vicious cycle is created when the initial injury causes muscular pain and spasm, which increases afferent nociceptive input to the spinal cord, further exciting the alpha motor neuron to cause more spasms, and so on.61,96 Other experts believe that muscle spasms occur because of a complex protective mechanism, whereby muscular contractions are intended to support an injured vertebral structure or peripheral joint.96 Regardless of the exact reason, tonic contraction of the affected muscle is often quite painful because of the buildup of pain-mediating metabolites (e.g., lactate). Consequently, various skeletal muscle relaxants attempt to decrease skeletal muscle excitation and contraction in cases of spasticity and spasm. Specific drugs and their mechanisms of action are discussed here.

decrease spasticity. One agent, diazepam (Valium), is indicated for both conditions and will appear in both categories. Finally, the use of botulinum toxin (Botox) as an alternative strategy for reducing focal spasms or spasticity will be addressed.

Agents Used to Treat Muscle Spasms

The effects of diazepam (Valium) on the CNS and its use as an antianxiety drug are discussed in Chapter 6. Basically, diazepam and other benzodiazepines work by increasing the central inhibitory effects of gammaaminobutyric acid (GABA); that is, diazepam binds to receptors located at GABAergic synapses and increases the GABA-induced inhibition at that synapse. Diazepam appears to work as a muscle relaxant through this mechanism, potentiating the inhibitory effect of GABA on alpha motor neuron activity in the spinal cord.40,102 The drug also exerts some supraspinal sedative effects; in fact, some of its muscle relaxant properties may derive from the drugs ability to produce a more generalized state of sedation.101 Uses. Diazepam is one of the oldest medications for treating muscle spasms, and has been used extensively in treating spasms associated with musculoskeletal injuries such as acute low-back strains. Diazepam has also been used to control muscle spasms associated with tetanus toxin; the use of valium in this situation can be life-saving as well by inhibiting spasms of the larynx and other muscles.51,65 Adverse Effects. The primary side effect with diazepam is that dosages successful in relaxing skeletal muscle also produce sedation and a general reduction in psychomotor ability.40,101 However, this effect may not be a problem and may actually be advantageous for the patient recovering from an acute musculoskeletal injury. For example, a patient with an acute lumbosacral strain may benefit from the sedative properties because he or she will remain fairly inactive, thereby allowing better healing during the first few days after the injury. Continued use, however, may be problematic because of diazepams sedative effects. The drug can also produce tolerance and physical dependence, and sudden withdrawal after prolonged use can cause seizures, anxiety, agitation, tachycardia, and even death.102 Likewise, an overdose with diazepam can result in coma or death as well.102 Hence, this

Specific Agents Used to Produce Skeletal Muscle Relaxation

Skeletal muscle relaxants are categorized in this chapter according to their primary clinical application: agents used to decrease spasms and agents used to

Chapter 13 Skeletal Muscle Relaxants


drug might be beneficial for the short-term management of acute muscle spasms, but long-term use should be discouraged.

Polysynaptic Inhibitors
A variety of centrally acting compounds have been used in an attempt to enhance muscle relaxation and decrease muscle spasms (see Table 131). Some examples are carisoprodol (Soma, Vanadom), chlorphenesin carbamate (Maolate), chlorzoxazone (Paraflex, Parafon Forte, others), cyclobenzaprine (Flexeril), metaxalone (Skelaxin), methocarbamol (Carbacot, Robaxin, Skelex), and orphenadrine citrate (Antiflex, Norflex, others). The mechanism of action of these drugs is not well defined.8 Research in animals has suggested that these drugs may decrease polysynaptic reflex activity in the spinal cord, hence the term polysynaptic inhibitors. A polysynaptic reflex arc in the spinal cord is comprised of several small interneurons that link incoming (afferent) input into the dorsal horn with outgoing (efferent) outflow onto the alpha motor neuron. By inhibiting the neurons in the polysynaptic pathways, these drugs could decrease alpha motor neuron excitability and therefore cause relaxation of skeletal muscle.

It is not clear, however, exactly how these drugs inhibit neurons involved in the polysynaptic pathways. There is preliminary evidence that one of these compounds (cyclobenzaprine) might block serotonin receptors on spinal interneurons, thereby decreasing the excitatory influence of serotonin on alpha motor neuron activity.50,55 Although this effect has been attributed to cyclobenzaprine in animals (rats), the effect of this drug and other muscle relaxants in humans remains to be determined. On the other hand, these compounds have a general depressant effect on the CNS; that is, they cause a global decrease in CNS excitability that results in generalized sedation. It therefore seems possible that some of their muscle relaxant effects are caused by their sedative powers rather than a selective effect on specific neuronal reflex pathways.11,92 This observation is not to say that they are ineffective, because clinical research has shown that these drugs can be superior to a placebo in producing subjective muscle relaxation.8,20,80,97 However, the specific ability of these drugs to relax skeletal muscle remains doubtful, and it is generally believed that their muscle relaxant properties are secondary to a nonspecific CNS sedation. Uses. These drugs are typically used as adjuncts to rest and physical therapy for the short-term relief of

Table 131


Usual Adult Oral Dosage (mg) 350 TID and bedtime Initially: 800 TID; reduce to 400 QID or less 250750 TID or QID Onset of Action (min) 30 Duration of Action (hr) 46

Carisoprodol (Soma, Vanadom) Chlorphenesin carbamate (Maolate) Chlorzoxazone (Paraflex, Parafon Forte, others) Cyclobenzaprine (Flexeril) Diazepam (Valium) Metaxalone (Skelaxin) Methocarbamol (Carbacot, Robaxin, Skelex) Orphenadrine citrate (Antiflex, Norflex, others)

Within 60


10 TID 210 TID or QID 800 TID or QID 1000 QID or 1500 TID

Within 60 1545 60 Within 30

1224 Variable 46 24

100 BID

Within 60



SECTION 3 Drugs Affecting Skeletal Muscle

muscle spasms associated with acute, painful musculoskeletal injuries.9,14,97 When used to treat spasms, these compounds are often given with a nonsteroidal anti-inflammatory agent (NSAIDs; see Chapter 15), or sometimes incorporated into the same tablet with an analgesic such as acetaminophen or aspirin. For instance, Norgesic is one of the brand names for orphenadrine combined with aspirin (and caffeine). Such combinations have been reported to be more effective than the individual components given separately.8 Adverse Effects. Because of their sedative properties, the primary side effects of these drugs are drowsiness and dizziness (see Table 132). A variety of additional adverse effects, including nausea, lightheadedness, vertigo, ataxia, and headache, may occur depending on the patient and the specific drug administered (Table 132). Cases of fatal overdose have also been documented for several of these drugs, including cyclobenzaprine and metaxolone.70,86 Long term or excessive use of these medications may also cause tolerance and physical dependence.14,31 In particular, carisoprodol should be used cautiously because this drug is metabolized in the body to form meprobamate, which is a controlled substance (see Chapter 1) that has sedative/anxiolytic properties but is not used extensively because it has strong potential for abuse.13,73 Hence, use of cariso-

prodol represents a rather unique situation where the drug itself or its metabolic byproduct (meprobamate) can produce effects and side effects that lead to addiction and abuse, especially in people with a history of substance abuse.13,73 Likewise, discontinuing carisoprodol suddenly after long term use can lead to withdrawal symptoms such as anxiety, tremors, muscle twitching, and hallucinations.72 Consequently, polysynaptic inhibitors can help provide short-term relief for muscle spasms associated with certain musculoskeletal conditions, and they may work synergistically with physical therapy and other interventions during acute episodes of back pain, neck pain, and so forth. Nonetheless, they have some rather serious side effects and potential for abuse, and the long-term use of these drugs should be discouraged.

Agents Used to Treat Spasticity

The three agents traditionally used in the treatment of spasticity are baclofen, diazepam, and dantrolene sodium (see Table 133, Fig. 132). Two newer agents, gabapentin and tizanidine, are also available for treating spasticity in various conditions. All of these agents are addressed below.

Table 132


Drowsiness M L M M M M L Dizziness or Lightheadedness L L M M M M L Headache L R L L M L L Nausea and Vomiting L R L L M L L

Drug Carisoprodol Chlorphenesin carbamate Chlorzoxazone Cyclobenzaprine Metaxalone Methocarbamol Orphenadrine citrate

Relative incidence of side effects: M more frequent; L less frequent; R rare. Taken from USP DI, 25th Edition. Copyright 2005.Thompson MICROMEDEX.

Chapter 13 Skeletal Muscle Relaxants


Table 133

Oral Dosage Adult: 5 mg TID initially; increase by 5 mg at 3-day intervals as required; maximum recommended dosage is 80 mg/day. Children: No specific pediatric dosage is listed; the adult dose must be decreased according to the size and age of the child. Adult: 25 mg/d initially; increase up to 100 mg 2, 3, or 4 times per day as needed; maximum recommended dose is 400 mg/day. Children (older than 5 yr of age): initially, 0.5 mg/kg body weight BID; increase total daily dosage by 0.5 mg/kg every 47 days as needed, and give total daily amount in 4 divided dosages; maximum recommended dose is 400 mg/d. Adult: 210 mg TID or QID. Children (older than 6 mo of age): 1.02.5 mg TID or QID (in both adults and children, begin at lower end of dosage range and increase gradually as tolerated and needed). Adult:* initially, 300 mg TID. Can be gradually increased up to 3600 mg/d based on desired response. Children* (312 years of age): Initially, 1015 mg/kg body weight in 3 divided dosages; increase over 3 days until desired effect or a maximum of 50 mg/kg/d. Adult: 8 mg every 68 hours as needed. Children: The safety and effficacy of this drug in treating spasticity in children have not been established. Comments More effective in treating spasticity resulting from spinal cord lesions (versus cerebral lesions).

Baclofen (Lioresal)

Dantrolene sodium (Dantrium)

Exerts an effect directly on the muscle cell; may cause generalized weakness in all skeletal musculature.

Diazepam (Valium)

Produces sedation at dosages that decrease spasticity.

Gabapentin (Neurontin)

Developed originally as an anticonvulsant; may also be helpful as an adjunct to other drugs in treating spasticity associated with spinal cord injury and multiple sclerosis.

Tizanidine (Zanaflex)

May reduce a in spinal cord disorders while producing fewer side effects and less generalized muscle weakness than other agents (oral baclofen, diazepam).

*Anticonvulsant dose

The chemical name of baclofen is beta (pchlorophenyl)-GABA. As this name suggests, baclofen is a derivative of the central inhibitory neurotransmitter GABA. However, there appear to be some differences between baclofen and GABA. Baclofen seems to

bind preferentially to certain GABA receptors, which have been classified as GABAb receptors (as opposed to GABAareceptors).64,95 Preferential binding to GABAb receptors enables baclofen to act as a GABA agonist, inhibiting transmission within the spinal cord at specific synapses.40,64 To put this in the context of its use as a muscle relaxant, baclofen appears to have an


SECTION 3 Drugs Affecting Skeletal Muscle

Diazepam Dantrolene



FIGURE 132 Structure of three primary antispasticity drugs.

inhibitory effect on alpha motor neuron activity within the spinal cord. This inhibition apparently occurs via inhibiting excitatory neurons that synapse with the alpha motor neuron (presynaptic inhibition), as well as directly affecting the alpha motor neuron itself (postsynaptic inhibition).40,102 The result is decreased firing of the alpha motor neuron, with a subsequent relaxation of the skeletal muscle. Uses. Baclofen is administered orally to treat spasticity associated with lesions of the spinal cord, including traumatic injuries resulting in paraplegia or quadriplegia and spinal cord demyelination resulting in MS.30,102 Baclofen is often the drug of choice in reducing the muscle spasticity associated with MS because it produces beneficial effects with a remarkable lack of adverse side effects when used in patients with MS.4 The drug also does not cause as much generalized muscle weakness as direct-acting relaxants such as dantrolene, which can be a major advantage of baclofen treatment in many patients with MS.101 Baclofen also appears to produce fewer side effects when used appropriately to reduce spasticity secondary to traumatic spinal cord lesions, thus providing a relatively safe and effective form of treatment.102 When administered systemically, baclofen is less effective in treating spasticity associated with supraspinal lesions (stroke, cerebral palsy), because these patients are more prone to the adverse side effects of this drug and because baclofen does not readily penetrate the blood-brain barrier.40,102 Oral baclofen has also been used to reduce alcohol consumption in people who are chronic alcohol abusers.21,22 Apparently, relatively low doses of baclofen can reduce the cravings and desire for alcohol consumption via the effects of this drug on CNS GABA receptors.21 Future studies will help clarify the role of this drug in treating chronic alcoholism. Adverse Effects. When initiating baclofen therapy, the most common side effect is transient drowsi-

ness, which usually disappears within a few days.30 When given to patients with spinal cord lesions, there are usually few other adverse effects. When given to patients who have had a CVA or to elderly individuals, there is sometimes a problem with confusion and hallucinations. Other side effects, occurring on an individual basis, include fatigue, nausea, dizziness, muscle weakness, and headache. Abrupt discontinuation of baclofen may also cause withdrawal symptoms such as hyperthermia, hallucinations, and seizures.30 Increased seizure activity has also been reported following baclofen overdose, and in selected patient populations such as certain children with cerebral palsy and certain adults with multiple sclerosis.48,81

Intrathecal Baclofen
Although baclofen is administered orally in most patients (Table 133) it can also be administered intrathecally in patients with severe, intractable spasticity.71,103 Intrathecal administration is the delivery of a drug directly into the subarachnoid space surrounding a specific level of the spinal cord. This places the drug very close to the spinal cord, thus allowing increased drug effectiveness with much smaller drug doses. Likewise, fewer systemic side effects occur because the drug tends to remain in the area of the cord rather than circulating in the bloodstream and causing adverse effects on other tissues. When baclofen is administered intrathecally for the long-term treatment of spasticity, a small catheter is usually implanted surgically so that the open end of the catheter is located in the subarachnoid space and the other end is attached to some type of programmable pump. The pump is implanted subcutaneously in the abdominal wall and is adjusted to deliver the drug at a slow, continuous rate. The rate of infusion is adjusted over time to achieve the best clinical reduction in spasticity.

Chapter 13 Skeletal Muscle Relaxants


Intrathecal baclofen delivery using implantable pumps has been used in patients with spasticity of spinal origin (spinal cord injury, multiple sclerosis),57,103 and in patients with spasticity resulting from supraspinal (cerebral) injury, including cerebral palsy, CVA, and traumatic brain injury.1,40,94 Studies involving these patients have typically noted a substantial decrease in rigidity (as indicated by decreased Ashworth scores, decreased reflex activity, and so forth).57,103 Patient satisfaction is generally favorable, and caregivers for younger children report ease of care following implantation of intrathecal baclofen pumps.17,43 There is growing evidence that intrathecal baclofen can also reduce pain of central origin in people with spasticity; that is, continuous baclofen administration to the subarachnoid space may inhibit the neural circuitry that induces chronic pain in people with stroke and other CNS injuries.85,90 Uses. Intrathecal baclofen can result in decreased spasticity and increased comfort in many people with severe spasticity. This intervention can also result in functional improvements, especially in cases where voluntary motor control was being masked by spasticity.16 Ambulatory patients with spasticity resulting from a CVA, for example, may be able to increase their walking speed and increase their functional mobility after intrathecal baclofen therapy.37,74 These functional improvements, however, may not occur in all types of spasticity. Patients with severe spasticity of spinal origin, for example, may not experience improvements in mobility or decreased disability.103 If these patients do not have adequate voluntary motor function there is simply not enough residual motor ability to perform functional tasks after spasticity is reduced. Nonetheless, these patients may still benefit from intrathecal baclofen because of decreased rigidity and pain, which can result in improved selfcare and the ability to perform daily living activities.37,74,76 Adverse effects. Despite these benefits, intrathecal baclofen is associated with a number of potential complications. Primary among these is the possibility of a disruption in the delivery system; that is, a pump malfunction or a problem with the delivery catheter can occur.42,60,67,69 In particular, the catheter can become obstructed, or the tip of the catheter can become displaced so that baclofen is not delivered into the correct area of the subarachnoid space. Increased drug delivery due to a pump malfunction could cause overdose and lead to respiratory depression, decreased cardiac function, and coma.40 Conversely, abruptly

stopping the drug due to pump failure, pump removal, or delivery catheter displacement/blockage may cause a withdrawal syndrome that includes fever, confusion, delirium, and seizures.46,75,104 A second major concern is the possibility that tolerance could develop with long-term, continuous baclofen administration. Tolerance is the need for more of a drug to achieve its beneficial effects when used for prolonged periods. Several studies have reported that dosage must indeed be increased progressively when intrathecal baclofen systems are used for periods of several months to several years.40,63 Tolerance to intrathecal baclofen, however, can usually be dealt with by periodic adjustments in dosage, and tolerance does not usually develop to such an extent that intrathecal baclofen must be discontinued. Hence, intrathecal baclofen offers a means of treating certain patients with severe spasticity who have not responded to more conventional means of treatment including oral baclofen. Additional research will help determine optimal ways that this intervention can be used to decrease spasticity. Further improvements in the technologic and mechanical aspects of intrathecal delivery, including better pumps and catheter systems, will also make this a safer and more practical method of treating these patients.

Dantrolene Sodium
The only muscle relaxant available that exerts its effect directly on the skeletal muscle cell is dantrolene sodium (Dantrium).40,102 This drug works by impairing the release of calcium from the sarcoplasmic reticulum within the muscle cell during excitation (Fig. 133).56,89 In response to an action potential, the release of calcium from sarcoplasmic storage sites initiates myofilament cross-bridging and subsequent muscle contraction. By inhibiting this release, dantrolene attenuates muscle contraction and therefore enhances relaxation. Uses. Dantrolene is often effective in treating severe spasticity, regardless of the underlying pathology.102 Patients with traumatic cord lesions, advanced MS, cerebral palsy, or CVAs will probably experience a reduction in spasticity with this drug. This drug is also invaluable in treating malignant hyperthermia, which is a potentially life-threatening reaction occurring in susceptible individuals following exposure to general anesthesia, muscle paralytics used during surgery, or certain antipsychotic medications (a condition also called neuroleptic malignant syndrome; see


SECTION 3 Drugs Affecting Skeletal Muscle

Sarcoplasmic Reticulum

Ca +

Ca ++


Contractile Filaments

FIGURE 133 Possible mechanism of action of dantrolene sodium (Dantrium). Dantrolene blocks channels in the sarcoplasmic reticulum, thus interfering with calcium release onto the contractile (actin, myosin) filaments. Muscle contraction is reduced because less calcium is available to initiate cross-bridge formation between actin and myosin filaments.

Chapter 8).2,58 In this situation, dantrolene inhibits skeletal muscle contraction throughout the body, thereby limiting the rise in body temperature generated by strong, repetitive skeletal muscle contractions.58 Dantrolene is not prescribed to treat muscle spasms caused by musculoskeletal injury. Adverse Effects. The most common side effect of dantrolene is generalized muscle weakness; this makes sense considering that dantrolene impairs sarcoplasmic calcium release in skeletal muscles throughout the body, not just in the hyperexcitable tissues. Thus, the use of dantrolene is sometimes counterproductive because the increased motor function that occurs when spasticity is reduced may be offset by generalized motor weakness. This drug may also cause severe hepatotoxicity, and cases of fatal hepatitis have been reported.20,102 The risk of toxic effects on the liver seems to be greater in women over 40 years of age, and in individuals receiving higher doses of this drug (over 300 mg).102 Other, less serious side effects that sometimes occur during the first few days of therapy include drowsiness, dizziness, nausea, and diarrhea, but these problems are usually transient.

Adverse effects. Use of diazepam as an antispasticity agent is limited by the sedative effects of this medication; that is, patients with spasticity who do not want a decrease in mental alertness will not tolerate diazepam therapy very well. Extended use of the drug can cause tolerance and physical dependence, and use of diazepam for the long-term treatment of spasticity should be avoided whenever possible.102

Developed originally as an antiseizure drug (see Chapter 9), gabapentin (Neurontin) has also shown some promise in treating spasticity. This drug appears to cause inhibition in the spinal cord in a manner similar to GABA, but the exact mechanism of this drug remains to be determined. That is, gabapentin does not appear to bind to the same receptors as GABA, and this drug does not appear to directly increase the release or effects of endogenous GABA.82,83 Nonetheless, gabapentin may decrease spasticity by raising the overall level of inhibition in the spinal cord, thereby decreasing excitation of the alpha motor neuron with subsequent skeletal muscle relaxation. The exact way that this drug exerts its antispasticity effects, however, remains to be determined. Uses. Gabapentin is effective in decreasing the spasticity associated with spinal cord injury102 and multiple sclerosis.29 Additional research should clarify how this drug can be used alone or with other agents to provide optimal benefits in spasticity resulting from various spinal, and possibly cerebral, injuries.

As indicated earlier, diazepam is effective in reducing spasticity as well as muscle spasms because this drug increases the inhibitory effects of GABA in the CNS. Uses. Diazepam is used in patients with spasticity resulting from cord lesions and is sometimes effective in patients with cerebral palsy.

Chapter 13 Skeletal Muscle Relaxants


Adverse effects. The primary side effects of this drug are sedation, fatigue, dizziness, and ataxia.

Tizanidine (Zanaflex) is classified as an alpha-2 adrenergic agonist, meaning that this drug binds selectively to the alpha-2 receptors in the CNS and stimulates them. Alpha-2 receptors are found at various locations in the brain and spinal cord, including the presynaptic and postsynaptic membranes of spinal interneurons that control alpha motor neuron excitability. Stimulation of these alpha-2 receptors inhibits the firing of interneurons that relay information to the alpha motor neuron; that is, interneurons that comprise polysynaptic reflex arcs within the spinal cord.27 Tizanidine appears to bind to receptors on spinal interneurons, decrease the release of excitatory neurotransmitters from their presynaptic terminals (presynaptic inhibition), and decrease the excitability of the postsynaptic neuron (postsynaptic inhibition).40 Inhibition of spinal interneurons results in decreased excitatory input onto the alpha motor neuron, with a subsequent decrease in spasticity of the skeletal muscle supplied by that neuron. Uses. Tizanidine has been used primarily to control spasticity resulting from spinal lesions (multiple sclerosis, spinal cord injury),40 and this drug may also be effective in treating spasticity in people with cerebral lesions (CVA, acquired brain injury).41,62 There is some concern, however, that tizanidine might slow neuronal recovery following brain injury, and some practitioners are therefore reluctant to use this drug during the acute phase of stroke or traumatic brain injury.102 Because it may inhibit pain pathways in the spinal cord, tizanidine has also been used to treat chronic headaches and other types of chronic pain (fibromyalgia, chronic regional pain syndromes, and so forth).77 As an antispasticity drug, tizanidine appears to be as effective as orally administered baclofen or diazepam, but tizanidine generally has milder side effects and produces less generalized muscle weakness than these other agents.40 Tizanidine is also superior to other alpha-2 agonists such as clonidine (Catapres) because tizanidine does not cause as much hypotension and other cardiovascular side effects. Clonidine exerts antispasticity as well as antihypertensive effects because this drug stimulates alpha-2 receptors in the cord and brainstem, respectively.102 Use of clonidine in treating spasticity, however, is limited because of the

cardiovascular side effects, and clonidine is used primarily for treating hypertension (see Chapter 21). Adverse Effects. The most common side effects associated with tizanidine include sedation, dizziness, and dry mouth.40 As indicated, however, tizanidine tends to have a more favorable side effect profile than other alpha-2 agonists, and this drug produces less generalized weakness than oral baclofen or diazepam. Tizanidine may therefore be a better alternative to these other agents in patients who need to reduce spasticity while maintaining adequate muscle strength for ambulation, transfers, and so forth.

Use of Botulinum Toxin as a Muscle Relaxant

Injection of botulinum toxin is a rather innovative way to control localized muscle hyperexcitability. Botulinum toxin is a purified version of the toxin that causes botulism. Systemic doses of this toxin can be extremely dangerous or fatal because botulinum toxin inhibits the release of acetylcholine from presynaptic terminals at the skeletal neuromuscular junction. Loss of presynaptic acetylcholine release results in paralysis of the muscle fiber supplied by that terminal. Systemic dissemination of botulinum toxin can therefore cause widespread paralysis, including loss of respiratory muscle function. Injection into specific muscles, however, can sequester the toxin within these muscles, thus producing localized effects that are beneficial in certain forms of muscle hyperexcitability. Mechanism of action. The cellular actions of botulinum toxin at the neuromuscular junction have recently been clarified.84 This toxin is attracted to glycoproteins located on the surface of the presynaptic terminal at the skeletal neuromuscular junction.33 Once attached to the membrane, the toxin enters the presynaptic terminal and inhibits proteins that are needed for acetylcholine release (Figure 134).84 Normally, certain proteins help fuse presynaptic vesicles with the inner surface of the presynaptic terminal, thereby allowing the vesicles to release acetylcholine via exocytosis. Botulinum toxin cleaves and destroys these fusion proteins, thus making it impossible for the neuron to release acetylcholine into the synaptic cleft.32,84 Local injection of botulinum toxin into specific muscles will therefore decrease muscle excitation by disrupting synaptic transmission at the neuromuscular junction. The affected muscle will invariably undergo some degree of paresis and subsequent


SECTION 3 Drugs Affecting Skeletal Muscle

Normal (no toxin)

Botulinum toxin

ACh vesicles


Fusion proteins



Skeletal Muscle Cell

FIGURE 134 Mechanism of action of botulinum toxin at the skeletal neuromuscular junction. At a normal synapse (shown on left), fusion proteins connect acetylcholine (ACh) vesicles with the presynaptic membrane, and ACh is released via exocytosis. Botulinum toxin (represented by BTX on the right) binds to the presynaptic terminal, and enters the terminal where it destroys the fusion proteins so that ACh cannot be released. See text for details.

relaxation because the toxin prevents the release of acetylcholine. It has been suggested that botulinum toxin might have other effects on neuronal excitability. This toxin, for example, might also inhibit contraction of intrafusal muscle fibers that are located within skeletal muscle, and help control sensitivity of the stretch reflex.33 Inhibiting these intrafusal fibers would diminish activity in the afferent limb of the stretch reflex, thereby contributing to the antispasticity effects of this intervention.33 Through its direct action on muscle excitability, botulinum toxin may also have other neurophysiological effects at the spinal cord level. That is, reducing spasticity might result in complex neurophysiologic changes at the spinal cord, ultimately resulting in more normal control of motor function in both the injected muscle and its antagonist.45 In other words, reduction of excessive afferent discharge from the spastic muscle might help reestablish a more reasonable level of excitation at the cord level, thus improving efferent discharge to the injected muscle and its antagonist.33,45 More research will be needed to help clarify how local administration of botulinum toxin can have direct effects on the injected muscle as well as reflex neurophysiological effects on the spinal cord. Clinical use of botulinum toxin. Seven strains (serotypes) of botulinum toxin have been identified,

but only two types are currently available for clinical use: botulinum toxin types A and B.15,23 These types differ somewhat in their chemistry, duration of action, and so forth. The most commonly used therapeutic type is botulinum toxin type A; this agent is marketed commercially under trade names such as Botox and Dysport. Botulinum toxin type B (Myobloc) is also available, and can be useful in patients who develop immunity to the type A form of this toxin (discussed later). Botulinum toxin has been used for some time to control localized muscle dystonias, including conditions such as spasmodic torticollis, blepharospasm, laryngeal dystonia, strabismus, and several other types of focal dystonias.6,25,26,87,93 When used therapeutically, small amounts of this toxin are injected directly into the dystonic muscles, which begin to relax within a few days to 1 week. This technique appears to be fairly safe and effective in many patients, but relief may only be temporary. Symptoms often return within 3 months after each injection, necessitating additional treatments.40 Still, this technique represents a method for treating patients with severe, incapacitating conditions marked by focal dystonias and spasms. More recently, there has been considerable interest in using botulinum toxin to reduce spasticity in specific muscles or muscle groups. This treatment has been used to treat spasticity resulting from various dis-

Chapter 13 Skeletal Muscle Relaxants


orders including cerebral palsy,10,68,78,99 traumatic brain injury,36,66,98 CVA,19,44,49 and spinal cord injury.39 As with treatment of focal dystonias, the toxin is injected directly into selected muscles. If necessary, electromyography or ultrasonography can be used to identify specific muscles and guide the injection to the desired site within the muscle belly (e.g., the motor point of the muscle).18,53,100 There is also some evidence that electrical stimulation of the nerve supplying the muscle for the first few days following injection may help increase the efficacy of the toxin, presumably by enhancing its uptake by the presynaptic nerve terminals.38 Botulinum toxin injection has been documented as a means to control severe spasticity in various clinical situations. This intervention, for example, can help remove spastic dominance in certain patients so that volitional motor function can be facilitated. For example, judicious administration of botulinum toxin can result in improved gait and other functional activities in selected patients with cerebral palsy, stroke, or traumatic brain injury.7,36,49,78 Even if voluntary motor function is not improved dramatically, reducing spasticity in severely affected muscles may produce other musculoskeletal benefits. For example, injection of botulinum toxin can reduce spasticity so that muscles can be stretched or casted more effectively, thus helping to prevent joint contractures and decreasing the need for surgical procedures such as heel-cord lengthening and adductor release.12,98 These injections can likewise enable patients to wear and use orthotic devices more effectively. Injection into the triceps surae musculature can improve the fit and function of an ankle-foot orthosis by preventing excessive plantar flexor spasticity from pistoning the foot out of the orthosis.49 Injections into severely spastic muscles can also increase patient comfort and ability to perform ADL and hygiene activities. Consider, for example, the patient with severe upper extremity flexor spasticity following a CVA. Local injection of botulinum toxin into the affected muscles may enable the patient to extend his or her elbow, wrist, and fingers, thereby allowing better hand cleansing, ability to dress, decreased pain, and so forth.7 Finally, local botulinum toxin administration has been advocated as a way to control muscle hyperexcitability in other clinical situations. There has, of course, been considerable interest in using this toxin for cosmetic reasons. Injection of botulinum toxin into specific facial muscles can paralyze these muscles, thereby reducing the appearance of wrinkles around the eyes, mouth, and so forth.3,24 Nonetheless,

patients undergoing physical rehabilitation may also benefit from uses of this toxin. For example, patients with hyperactive (neurogenic) bladder following spinal cord injury can be treated by injecting botulinum toxin directly into the bladder detrussor muscle or external urethral sphincter.28,59 This intervention may help normalize bladder function and promote more effective voiding.28,47 Botulinum toxin has also been used to treat patients with chronic pain syndromes, including chronic headache, migraine, and various musculoskeletal disorders (back pain, whiplash injuries, and so forth).24,88 Clearly, this intervention has many potential benefits in many different clinical situations, and additional research will be needed to document how botulinum toxin can be used to reduce muscle hyperexcitability and improve function in various patient populations. Limitations and side effects. Botulinum toxin does not cure spasticity and there are a number of limitations to its use. In particular, only a limited number of muscles can be injected during a given treatment because only a limited amount of botulinum toxin can be administered during each set of injections. For example, the total amount of botulinum toxin type A injected during each treatment session is typically between 200300 units in adults, with proportionally smaller amounts used in children depending on his or her size and age.40 The typical dose of the type B form is 25005000 units. Exceeding these doses will cause an immune response whereby antibodies are synthesized against the toxin, making subsequent treatments ineffective because the patients immune system will recognize and inactivate the toxin.34,35,91 The number of muscles that can be injected is therefore often limited to one or two muscle groups; for example, the elbow and wrist flexors in one upper extremity of an adult, or the bilateral triceps surae musculature of a child. As indicated earlier, the relaxant effects of the toxin are likewise temporary, and these effects typically diminish within 2 to 3 months after injection.91 The effects apparently wear off because a new presynaptic terminal sprouts from the axon that contains the originally affected presynaptic terminal. This new terminal grows downward, reattaching to the skeletal muscle and creating a new motor end plate with a new source of acetylcholine. The effects of the previous injection are overcome when this new presynaptic terminal begins to function. Another injection will be needed to block the release from this new presynaptic terminal, thus allowing another 2 to 3 months of antispasticity effects. This fact raises the question of how


SECTION 3 Drugs Affecting Skeletal Muscle

many times the injection cycle can be repeated safely and effectively. At the present time, there is no clear limit to the number of times a muscle can be injected, providing, of course, that sufficient time has elapsed between each series of injections.5 Longitudinal studies will be needed to determine if there are any detrimental effects of long-term use of this intervention. Consequently, botulinum toxin represents a strategy for dealing with spasticity that is especially problematic in specific muscles or groups of muscles. Despite the rather ominous prospect of injecting a potentially lethal toxin into skeletal muscles, this intervention has a remarkably small incidence of severe adverse effects when administered at therapeutic doses.5,44 Botulinum toxin can therefore be used as part of a comprehensive rehabilitation program to provide optimal benefits in certain patients with severe spasticity.

Most muscle relaxants are absorbed fairly easily from the gastrointestinal tract, and the oral route is the most frequent method of drug administration. In cases of severe spasms, certain drugs such as methocarbamol and orphenadrine can be injected intramuscularly or intravenously to permit a more rapid effect. Likewise, diazepam and dantrolene can be injected to treat spasticity if the situation warrants a faster onset. As discussed earlier, continuous intrathecal baclofen administration may be used in certain patients with severe spasticity, and local injection of botulinum toxin is a possible strategy for treating focal dystonias and spasticity. Metabolism of muscle relaxants is usually accomplished by hepatic microsomal enzymes; and the metabolite or intact drug is excreted through the kidneys.

Special Concerns in Rehabilitation Patients

Because of the very nature of their use, skeletal muscle relaxants are prescribed for many patients involved in rehabilitation programs. Physical therapists and other rehabilitation professionals will encounter these drugs applied as both antispasm and antispasticity agents. When used to reduce muscle spasms following nerve root impingements, muscle strains, and the like, these drugs will complement the physical therapy interventions. Concomitant use of muscle relaxants with thermal, electrotherapeutic, and manual techniques can produce optimal benefits during the acute phase of musculoskeletal injuries causing spasms. Of course, the long-term use of antispasm agents is not practical because these drugs often cause sedation, and they can have addictive properties that lead to tolerance and physical dependence. This fact further emphasizes the need for aggressive physical therapy so that the drugs can be discontinued as soon as possible. Physical therapists and occupational therapists can also help prevent reinjury and recurrence of spasms by improving the patients muscle strength, flexibility, posture, and by teaching proper body mechanics and lifting techniques. These interventions may help decrease the incidence of spasms and the need for drugs used to treat them. The pharmacologic reduction of spasticity is also an important goal in patients receiving physical therapy and occupational therapy. As indicated earlier, decreased spasticity can result in increased motor function, easier self-care or nursing care, and decreased painful and harmful effects of strong spastic contractions. Drug treatment is likewise synergistic with rehabilitation; that is, antispasticity agents can allow more effective passive range-of-motion and stretching activities, as well as permit more effective use of neuromuscular facilitation techniques, orthotic devices, and other interventions designed to reduce spasticity and improve function. Rehabilitation specialists also play a critical role in helping patients adapt to sudden changes in muscle excitability caused by antispasticity drugs. Reducing spasticity may, in fact, adversely affect the individual relying on increased muscle tone to assist in functional activities

Chapter 13 Skeletal Muscle Relaxants


such as ambulation. For example, patients who have had a CVA and use extensor spasticity in the lower extremity to support themselves when walking may begin to fall if this spasticity is reduced suddenly by drugs. This loss of support from the hypertonic muscles will hopefully be replaced by a more normal form of motor function. Therapists can therefore play a vital role in facilitating the substitution of normal physiologic motor control for the previously used spastic tone. This idea seems especially true when one of the parenteral antispasticity techniques is used, such as intrathecal baclofen or botulinum toxin injections. For example, patients who receive intrathecal baclofen through programmable pump systems often require a period of intensive rehabilitation to enable the benefits from decreased spasticity and increased voluntary motor function to occur. Therapists must therefore be ready to use aggressive rehabilitation techniques to help patients adapt to the relatively rapid and dramatic decrease in muscle tone that is often associated with antispasticity drug therapy. Rehabilitation specialists can also play a critical role in using certain antispasticity drugs effectively. In particular, therapists can help identify patients who are suitable candidates for botulinum toxin injections, and help evaluate these patients pre-injection and postinjection to determine if they achieved the desired outcomes. Rehabilitation specialists are, in fact, often in the best position to evaluate the effects of all antispasticity drugs. By working closely with the patient, the patients family, and the physician, therapists can provide valuable feedback about the efficacy of antispasticity drugs and whether they are helping to produce improvements in the patients function and well-being. Finally, therapists may have to deal with the side effects of these drugs. Depending on the drug in question, problems with sedation, generalized muscle weakness, and hepatotoxicity can negate any beneficial effects from a reduction in muscle tone. Sedation, which may occur to a variable degree with all systemic skeletal muscle relaxants, must sometimes be accommodated in the rehabilitation program. If the patient needs to be awake and alert, treatments may have to be scheduled at a time of the day when the sedative effects are minimal. In situations of generalized muscle weakness (i.e., during the use of dantrolene sodium or oral baclofen), there is often little that the physical therapist can do to resolve this problem. For instance, the patient with paraplegia who requires adequate upper extremity strength to perform transfers, wheelchair mobility, and ambulation with crutches and braces may find his or her ability to perform these activities compromised by the antispasticity drug. The role of the therapist in this situation may simply be to advise the patient that voluntary muscular power is limited and that some upper extremity strength deficits can be expected. The therapist may also work closely with the physician in trying to find the minimum acceptable dose for that patient or in attempting to find a better drug (e.g., switching from dantrolene to tizanidine).

Muscle Relaxants
Brief History. F.D. is a 28-year-old man who sustained complete paraplegia below the L-2 spinal level during an automobile accident. Through the course of rehabilitation he was becoming independent in self-care, and he had begun to ambulate in the parallel bars and with crutches while wearing temporary long leg braces. He was highly motivated to continue this progress and was eventually fitted with permanent leg orthoses. During this period, spasticity had increased in his lower extremities to the point where dressing and self-care were often difficult. Also, the ability of the patient to put his leg braces on was often compromised by lower extremity spasticity. The patient was started on oral baclofen (Lioresal) at an initial oral dosage of 15 mg/day. The daily dosage of baclofen was gradually increased until he was receiving 60 mg/day.


SECTION 3 Drugs Affecting Skeletal Muscle

Problem/Influence of Medication. Although the baclofen was effective in controlling his spasticity, F.D. began to notice weakness in his arms and upper torso when he attempted to ambulate and transfer. This decrease in voluntary power in his upper extremities was caused by the generalized muscle weakness sometimes seen when this drug is used.

Decision/Solution. The therapist conferred with the patients physician, and the decreased voluntary muscle power was noted. As an alternative, the patient was switched to tizanidine (Zanaflex). The dosage was adjusted until the spasticity was adequately reduced, and no further problems were noted.

Skeletal muscle relaxants are used to treat the muscle spasms that result from musculoskeletal injuries or spasticity that occurs following lesions in the CNS. Depending on the specific agent, these drugs reduce muscle excitability by acting on the spinal cord, at the neuromuscular junction, or directly within the skeletal muscle fiber. Diazepam and polysynaptic inhibitors are used in the treatment of muscle spasms, but their effectiveness as muscle relaxants may be because of their nonspecific sedative properties. Agents used to treat spasticity include baclofen, dantrolene, diazepam, gabapentin, and tizanidine. Each drug works by a

somewhat different mechanism, and the selection of a specific antispasticity agent depends on the patient and the underlying CNS lesion (e.g., stroke, MS). Local injection of botulinum toxin can also be used to treat focal dystonias and spasticity, and this technique may help control spasms and spasticity in specific muscles or muscle groups. Physical therapists and other rehabilitation personnel will frequently work with patients taking these drugs for the treatment of either spasticity or spasms. Although there are some troublesome side effects, these drugs generally facilitate the rehabilitation program by directly providing benefits (muscle relaxation) that are congruent with the major rehabilitation goals.

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35. 36.



baclofen therapy: a preliminary study. Arch Phys Med Rehabil. 2003;84:11941199. Frasson E, Priori A, Ruzzante B, et al. Nerve stimulation boosts botulinum toxin action in spasticity. Mov Disord. 2005;20:624629. Fried GW, Fried KM. Spinal cord injury and use of botulinum toxin in reducing spasticity. Phys Med Rehabil Clin N Am. 2003;14:901910. Gallichio JE. Pharmacologic management of spasticity following stroke. Phys Ther. 2004;84:973981. Gelber DA, Good DC, Dromerick A, et al. Open-label dose-titration safety and efficacy study of tizanidine hydrochloride in the treatment of spasticity associated with chronic stroke. Stroke. 2001;32:18411846. Gooch JL, Oberg WA, Grams B, et al. Complications of intrathecal baclofen pumps in children. Pediatr Neurosurg. 2003;39:16. Gooch JL, Oberg WA, Grams B, et al. Care provider assessment of intrathecal baclofen in children. Dev Med Child Neurol. 2004;46:548552. Gordon MF, Brashear A, Elovic E, et al. Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke. Neurology. 2004;63:19711973. Gracies JM. Physiological effects of botulinum toxin in spasticity. Mov Disord. 2004;19(suppl 8):S120S128. Greenberg MI, Hendrickson RG. Baclofen withdrawal following removal of an intrathecal baclofen pump despite oral baclofen replacement. J Toxicol Clin Toxicol. 2003;41:8385. Hajebrahimi S, Altaweel W, Cadoret J, et al. Efficacy of botulinum-A toxin in adults with neurogenic overactive bladder: initial results. Can J Urol. 2005;12: 25432546. Hansel DE, Hansel CR, Shindle MK, et al. Oral baclofen in cerebral palsy: possible seizure potentiation? Pediatr Neurol. 2003;29:203206. Hesse S. Recovery of gait and other motor functions after stroke: novel physical and pharmacological treatment strategies. Restor Neurol Neurosci. 2004;22: 359369. Honda M, Nishida T, Ono H. Tricyclic analogs cyclobenzaprine, amitriptyline and cyproheptadine inhibit the spinal reflex transmission through 5-HT(2) receptors. Eur J Pharmacol. 2003;458:9199. Ismoedijanto, Nassiruddin M, Prajitno BW. Case report: diazepam in severe tetanus treatment. Southeast Asian J Trop Med Public Health. 2004;35:175180. Ivanhoe CB, Reistetter TA. Spasticity: the misunderstood part of the upper motor neuron syndrome. Am J Phys Med Rehabil. 2004;83(suppl):S3S9. Kinnett D. Botulinum toxin A injections in children: technique and dosing issues. Am J Phys Med Rehabil. 2004;83(suppl):S59S64. Kita M, Goodkin DE. Drugs used to treat spasticity. Drugs. 2000;59:487495. Kobayashi H, Hasegawa Y, Ono H. Cyclobenzaprine, a centrally acting muscle relaxant, acts on descending serotonergic systems. Eur J Pharmacol. 1996;311: 2935. Kobayashi S, Bannister ML, Gangopadhyay JP, et al. Dantrolene stabilizes domain interactions within the ryanodine receptor. J Biol Chem. 2005;280:65806587.


SECTION 3 Drugs Affecting Skeletal Muscle the pump reservoir: a report of 2 cases. Arch Phys Med Rehabil. 2004;85:20642066. Sampson FC, Hayward A, Evans G, et al. Functional benefits and cost/benefit analysis of continuous intrathecal baclofen infusion for the management of severe spasticity. J Neurosurg. 2002;96:10521057. Saper JR, Lake AE, 3rd, Cantrell DT, et al. Chronic daily headache prophylaxis with tizanidine: a doubleblind, placebo-controlled, multicenter outcome study. Headache. 2002;42:470482. Sarioglu B, Serdaroglu G, Tutuncuoglu S, Ozer EA. The use of botulinum toxin type A treatment in children with spasticity. Pediatr Neurol. 2003;29: 299301. Satkunam LE. Rehabilitation medicine: 3. Management of adult spasticity. CMAJ. 2003;169:11731179. Schnitzer TJ, Ferraro A, Hunsche E, Kong SX. A comprehensive review of clinical trials on the efficacy and safety of drugs for the treatment of low back pain. J Pain Symptom Manage. 2004;28:7295. Schuele SU, Kellinghaus C, Shook SJ, et al. Incidence of seizures in patients with multiple sclerosis treated with intrathecal baclofen. Neurology. 2005;64: 10861087. Shimizu S, Honda M, Tanabe M, et al. Endogenous GABA does not mediate the inhibitory effects of gabapentin on spinal reflexes in rats. J Pharmacol Sci. 2004;94:137143. Shimizu S, Honda M, Tanabe M, Ono H. GABA B receptors do not mediate the inhibitory actions of gabapentin on the spinal reflex in rats. J Pharmacol Sci. 2004;96:444449. Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol. 2004; 44:167193. Slonimski M, Abram SE, Zuniga RE. Intrathecal baclofen in pain management. Reg Anesth Pain Med. 2004;29:269276. Spiller HA, Cutino L. Fatal cyclobenzaprine overdose with postmortem values. J Forensic Sci. 2003;48: 883884. Sulica L. Contemporary management of spasmodic dysphonia. Curr Opin Otolaryngol Head Neck Surg. 2004;12:543548. Sycha T, Kranz G, Auff E, Schnider P. Botulinum toxin in the treatment of rare head and neck pain syndromes: a systematic review of the literature. J Neurol. 2004;251(suppl 1):I19I30. Szentesi P, Collet C, Sarkozi S, et al. Effects of dantrolene on steps of excitation-contraction coupling in mammalian skeletal muscle fibers. J Gen Physiol. 2001; 118:355375. Taira T, Hori T. Clinical application of drug pump for spasticity, pain, and restorative neurosurgery: other clinical applications of intrathecal baclofen. Acta Neurochir Suppl. 2003;87:3738. Tilton AH. Injectable neuromuscular blockade in the treatment of spasticity and movement disorders. J Child Neurol. 2003;18(suppl 1):S50S66. Toth PP, Urtis J. Commonly used muscle relaxant therapies for acute low back pain: a review of cariso-

57. Korenkov AI, Niendorf WR, Darwish N, et al. Continuous intrathecal infusion of baclofen in patients with spasticity caused by spinal cord injuries. Neurosurg Rev. 2002;25:228230. 58. Krause T, Gerbershagen MU, Fiege M, et al. Dantrolenea review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004;59:364373. 59. Leippold T, Reitz A, Schurch B. Botulinum toxin as a new therapy option for voiding disorders: current state of the art. Eur Urol. 2003;44:165174. 60. Lew SM, Psaty EL, Abbott R. An unusual cause of overdose after baclofen pump implantation: case report. Neurosurgery. 2005;56:E624. 61. Maigne JY, Vautravers P. Mechanism of action of spinal manipulative therapy. Joint Bone Spine. 2003; 70:336341. 62. Meythaler JM, Guin-Renfroe S, Johnson A, Brunner RM. Prospective assessment of tizanidine for spasticity due to acquired brain injury. Arch Phys Med Rehabil. 2001;82:11551163. 63. Nielsen JF, Hansen HJ, Sunde N, Christensen JJ. Evidence of tolerance to baclofen in treatment of severe spasticity with intrathecal baclofen. Clin Neurol Neurosurg. 2002;104:142145. 64. Ohliger-Frerking P, Wiebe SP, Staubli U, Frerking M. GABA(B) receptor-mediated presynaptic inhibition has history-dependent effects on synaptic transmission during physiologically relevant spike trains. J Neurosci. 2003;23:48094814. 65. Okoromah CN, Lesi FE. Diazepam for treating tetanus. Cochrane Database Syst Rev. 2004;CD003954. 66. OSuilleabhain P, Dewey RB, Jr. Movement disorders after head injury: diagnosis and management. J Head Trauma Rehabil. 2004;19:305313. 67. Pasquier Y, Cahana A, Schnider A. Subdural catheter migration may lead to baclofen pump dysfunction. Spinal Cord. 2003;41:700702. 68. Pidcock FS. The emerging role of therapeutic botulinum toxin in the treatment of cerebral palsy. J Pediatr. 2004;145(suppl 2):S33S35. 69. Plassat R, Perrouin Verbe B, Menei P, et al. Treatment of spasticity with intrathecal Baclofen administration: long-term follow-up, review of 40 patients. Spinal Cord. 2004;42:686693. 70. Poklis JL, Ropero-Miller JD, Garside D, Winecker RE. Metaxalone (Skelaxin)-related death. J Anal Toxicol. 2004;28:537541. 71. Rawlins PK. Intrathecal baclofen therapy over 10 years. J Neurosci Nurs. 2004;36:322327. 72. Reeves RR, Beddingfield JJ, Mack JE. Carisoprodol withdrawal syndrome. Pharmacotherapy. 2004;24: 18041806. 73. Reeves RR, Carter OS, Pinkofsky HB, et al. Carisoprodol (soma): abuse potential and physician unawareness. J Addict Dis. 1999;18:5156. 74. Remy-Neris O, Tiffreau V, Bouilland S, Bussel B. Intrathecal baclofen in subjects with spastic hemiplegia: assessment of the antispastic effect during gait. Arch Phys Med Rehabil. 2003;84:643650. 75. Rigoli G, Terrini G, Cordioli Z. Intrathecal baclofen withdrawal syndrome caused by low residual volume in




79. 80.




84. 85. 86. 87. 88.



91. 92.

Chapter 13 Skeletal Muscle Relaxants prodol, cyclobenzaprine hydrochloride, and metaxalone. Clin Ther. 2004;26:13551367. Truong D, Duane DD, Jankovic J, et al. Efficacy and safety of botulinum type A toxin (Dysport) in cervical dystonia: results of the first US randomized, doubleblind, placebo-controlled study. Mov Disord. 2005; 20:783791. Turner MS. Early use of intrathecal baclofen in brain injury in pediatric patients. Acta Neurochir Suppl. 2003;87:8183. Vacher CM, Bettler B. GABA(B) receptors as potential therapeutic targets. Curr Drug Targets CNS Neurol Disord. 2003;2:248259. van Dieen JH, Selen LP, Cholewicki J. Trunk muscle activation in low-back pain patients, an analysis of the literature. J Electromyogr Kinesiol. 2003;13: 333351. van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev. 2003;CD004252. Verplancke D, Snape S, Salisbury CF, et al. A randomized controlled trial of botulinum toxin on lower limb spasticity following acute acquired severe brain injury. Clin Rehabil. 2005;19:117125.



94. 95. 96.

97. 98.

99. Wasiak J, Hoare B, Wallen M. Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy. Cochrane Database Syst Rev. 2004;CD003469. 100. Westhoff B, Seller K, Wild A, et al. Ultrasoundguided botulinum toxin injection technique for the iliopsoas muscle. Dev Med Child Neurol. 2003;45: 829832. 101. White PF, Katzung BG. Skeletal muscle relaxants. In Katzung BG, ed. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw Hill; 2004. 102. Zafonte R, Lombard L, Elovic E. Antispasticity medications: uses and limitations of enteral therapy. Am J Phys Med Rehabil. 2004;83(suppl):S50S58. 103. Zahavi A, Geertzen JH, Middel B, et al. Long term effect (more than five years) of intrathecal baclofen on impairment, disability, and quality of life in patients with severe spasticity of spinal origin. J Neurol Neurosurg Psychiatry. 2004;75:15531557. 104. Zuckerbraun NS, Ferson SS, Albright AL, Vogeley E. Intrathecal baclofen withdrawal: emergent recognition and management. Pediatr Emerg Care. 2004;20: 759764.

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Drugs Used to Treat Pain and Inf lammation

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Opioid Analgesics
Analgesic drug therapy and certain rehabilitation interventions share a common goal: pain relief. Consequently, analgesics are among the drugs most frequently taken by patients who are treated in a rehabilitation setting. The vast array of drugs that are used to treat pain can be roughly divided into two categories: opioid and nonopioid analgesics. Nonopioid analgesics are composed of drugs such as acetaminophen, aspirin, and similar agents. These drugs are discussed in Chapter 15. Opioid analgesics are a group of naturally occurring, semisynthetic, and synthetic agents that are characterized by their ability to relieve moderate-to-severe pain. These drugs exert their effects by binding to specific neuronal receptors that are located primarily in the central nervous system (CNS). Opioid analgesics are also characterized by their potential ability to produce physical dependence, and these agents are classified as controlled substances in the United States because of their potential for abuse (see Chapter 1 for a description of controlled substance classification). Morphine (Fig. 141) is considered the prototypical opioid analgesic, and other drugs of this type are often compared to morphine in terms of efficacy and potency.44,65 In the past, the term narcotic was often applied to these compounds becausewhen takenthey tend to have sedative or sleep-inducing side effects and high doses can produce a state of unresponsiveness and stupor. Narcotic is a misleading name, however, because it describes a side effect rather than their principal therapeutic effect. Likewise, these drugs are frequently referred to as opiate analgesics because some of these compounds are derived from opium (see the next section, Source of Opioid Analgesics). More recently, the term opioid has also been instituted to represent all types of narcotic analgesiclike agents, regardless of their origin.27 Hence, most sources preferentially use the term opioid to describe these drugs, and clinicians should recognize that this term represents all of the morphinelike medications.

Source of Opioid Analgesics

As mentioned previously, opioid analgesics can be obtained from natural, synthetic, or semisynthetic sources. Synthetic agents, as the designation implies, are simply formulated from basic chemical components in the laboratory. The source of naturally occurring and semisynthetic narcotic analgesics is from the opium poppy.27,65 When the extract from the seeds of this flower is allowed to dry and harden, the resulting substance is opium. Opium contains about 20 biologically active compounds, including morphine and codeine. Other derivatives from opium can also directly produce analgesia in varying degrees or can serve as precursors for analgesic drugs. The most notable of these precursors is thebaine, which can be modified chemically to yield compounds such as heroin. Likewise, semisynthetic narcotic analgesics are derived from these precursors. Semisynthetic opioids can also


O HO Morphine
FIGURE 141 Structure of morphine.



SECTION 4 Drugs Used to Treat Pain and Inflammation

be formulated by modifying one of the other naturally occurring narcotic drugs, such as morphine. In addition to analgesic drugs and their precursors, opium also contains compounds that do not have any analgesic properties. These compounds can actually antagonize the analgesic effects of opioid agonists such as morphine. (As defined in Chapter 4, an agonist stimulates its respective receptor and exerts a physiologic response, whereas an antagonist blocks the receptor, thus preventing the response.) The role of these opioid antagonists is discussed in Classification of Specific Agents, later in this chapter.

exogenous drugs influence the function of the endogenous peptides, and vice versa.25,63

Opioid Receptors
Since their discovery, the opioid receptors have been examined in considerable detail. Studies in animals have suggested that rather than only one homogeneous opioid receptor, there are at least three primary classes known as mu, kappa, and delta receptors69,82 (Table 141). Some sources also divide these primary classes into subcategories (i.e., mu1, mu2, delta1, delta2, kappa1, kappa2, kappa3) based on how well various opioids affect these receptors.65 The significance of these subcategories, however, has been questioned somewhat based on studies using opioid receptors that were cloned from rodent cell lines.27 That is, it is not clear at the present time if the primary classes (mu, kappa, delta) can be subclassified based on structural or functional differences within each primary receptor class.27 Nonetheless, mu opioid receptors are somewhat distinct from kappa receptors, and kappa receptors are distinct from delta receptors, and so forth. Hence, some specialization regarding both the location and the response of specific primary classes of opioid receptors does appear to exist (see Table 141). Stimulation of all three classes of opioid receptors causes analgesia. The mu receptor, however, seems to be the most important in mediating the analgesic effects of many opioids, including morphine.30,33 Mu receptors are located in specific locations in the brain and spinal cord, and opioids that are used clinically to reduce pain typically have a fairly high affinity for the mu class of opioid receptors.27 Unfortunately, some of the more problematic side effects of opioid drugs may also be mediated by stimulation of mu receptors. For example, stimulation of mu receptors may also cause respiratory depression and constipation, and repeated stimulation of mu opioid receptors has been associated with the cellular changes that might lead to opioid abuse and addiction.15,27 The existence of several classes of opioid receptors has therefore lead to the development of drugs that are somewhat more selective in the receptor class or subclass that they stimulate. In particular, drugs that selectively stimulate kappa or delta receptors may still provide sufficient analgesia, but will be less likely to provoke problems like respiratory depression and opioid abuse if they avoid or even block (antagonize) the mu receptors. Certain opioid drugs, for example, stimulate kappa receptors while avoiding or blocking

Endogenous Opioid Peptides and Opioid Receptors

Endogenous Opioids
Neurons at specific locations within the brain and spinal cord have been identified as having receptors that serve as binding sites for morphine and other similar exogenous substances.27 Exogenous opioids exert their effects by binding to these receptors; the proposed mechanisms of these drug-receptor interactions are discussed later in Mechanism of Action. The discovery of these opioid receptors also suggested the existence of an endogenous opioidlike substance. Rather than isolating one such compound, the search for an endogenous morphine has actually revealed several groups of peptides with analgesic and other pharmacologic properties. It is now recognized that three distinct families of endogenous opioids exist: the endorphins, enkephalins, and dynorphins.27,72 These peptides are manufactured and released within the body to control pain under specific conditions.29,65,81 Endogenous opioids are also released during other stressful situations, and these endogenous peptides interact with other neurochemicals (e.g., melatonin) and the immune system to help individuals deal with various types of physical and psychological stress.23,66,67,85 This chapter is not intended to elucidate all of the known details of the endogenous opioid peptide system or to illustrate how these endogenous compounds can be influenced by opioid drugs. The endogenous compounds described do exert their effects, however, via the same receptors as the exogenous opioid drugs. Obviously, there is the possibility for a great deal of interaction between the endogenous and exogenous opioids, and researchers continue to investigate how

Chapter 14 Opioid Analgesics


Table 141
Receptor Class Mu ( )

Primary Therapeutic Effect(s) Spinal and supraspinal analgesia Other Effects Sedation; respiratory depression; constipation; inhibits neurotransmitter release (acetylcholine, dopamine); increases hormonal release (prolactin; growth hormone) Sedation; constipation; psychotic effects Increases hormonal release (growth hormone); inhibits neurotransmitter release (dopamine)

Kappa ( ) Delta ( )

Spinal and supraspinal analgesia Spinal and supraspinal analgesia

Adapted from Gutstein and Akil,27 page 573.

the mu receptors. These agents are known as mixed agonist-antagonist opioids and their clinical significance is addressed in the next section, Classification of Specific Agents. The discovery of several classes of opioid receptors that cause different effects and side effects has important pharmacologic implications. Research in this area continues to expand our knowledge about the structural and functional aspects of these receptor classes. Drug developers will hopefully capitalize on the unique aspects of opioid receptor classes, and new agents will be produced that are even more specific in relieving pain without provoking excessive side effects.

levorphanol (Levo-Dromoran) meperidine (Demerol) methadone (Dolophine, Methadose) morphine (MS Contin, Roxanol, Statex, others) oxymorphone (Numorphan)

Mild-to-Moderate Agonists. These drugs are still considered agonists that stimulate opioid receptors, but they do not have as high an affinity or efficacy as the drugs listed previously. These drugs are more effective in treating pain of moderate intensity. Examples include the following: codeine hydrocodone (Hycodan) oxycodone (OxyContin, Roxicodone) propoxyphene (Darvon)

Classification of Specific Agents

Opioid analgesics are classified as strong agonists, mild-to-moderate agonists, mixed agonist-antagonists, and antagonists according to their interaction with opioid receptors. Some of the opioids in these categories are listed in Table 142. The basic characteristics of each category and clinically relevant examples are also discussed here. Strong Agonists. These agents are used to treat severe pain. As the name implies, these drugs have a high affinity for certain receptors and are believed to interact primarily with mu opioid receptors in the CNS. The best-known member of this group is morphinethe other strong agonists are pharmacologically similar. Examples of strong opioid agonists include the following: fentanyl (Actiq, Duragesic, Sublimaze) hydromorphone (Hydrostat, Dilaudid)

Mixed Agonist-Antagonists. These drugs exhibit some agonist and antagonistlike activity at the same time because the drugs have the ability to act differently at specific classes of opioid receptors. For instance, certain drugs in this category (butorphanol, nalbuphine, pentazocine) cause analgesia because they bind to and activate kappa receptors; that is, they are kappa receptor agonists. At the same time, these drugs block or only partially activate mu receptors, thus acting as mu receptor antagonists or partial agonists, respectively27 (the effects of partial agonists are described in more detail in Chapter 4). Mixed agonistantagonist opioids appear to have the advantage of producing adequate analgesia with less risk of the side effects associated with mu receptors, including respiratory depression. These drugs are therefore safer in terms of a reduced risk of fatal overdose.27 These drugs may also have fewer addictive qualities than strong mu receptor agonists such as morphine.27 Mixed agonist-


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Table 142

Route of Administration* IM IV Oral IM IV Sub-Q Oral IM IV Sub-Q Oral IM IV Sub-Q Oral IM IV Oral IM IV Sub-Q Epidural Intrathecal Rectal IM IV Sub-Q Rectal Onset of Action (min) 715 12 30 15 1015 15 1060 15 1015 1 1015 3060 1020 1030 1030 1560 1560 2060 1015 510 1020 1530 Time to Peak Effect (min) 2030 35 90120 3060 1530 3090 90120 60 Within 20 6090 6090 3050 57 3050 90120 60120 1530 60120 3060 20 5090 3090 1530 120 Duration of Action (hr) 12 0.51 4 45 23 4 45 45 45 45 24 24 24 24 46 45 34 45 45 45 45 Up to 24 Up to 24 36 34 36 36

Strong Agonists Fentanyl (Sublimaze)

Hydromorphone (Hydrostat, Dilaudid)

Levorphanol (Levo-Dromoran)

Meperidine (Demerol)

Methadone (Dolophine, Methadose)

Morphine (many trade names)

Oxymorphone (Numorphan)

Mild-to-Moderate Agonists Codeine (generic) Oral IM Sub-Q Oral Oral Oral 3045 1030 1030 1030 1560 60120 3060 3060 60 120 4 4 4 46 34 46

Hydrocodone (Hycodan) Oxycodone (OxyContin, Roxicodone) Propoxyphene (Darvon)

Chapter 14 Opioid Analgesics


Drug Butorphanol (Stadol)

Route of Administration* IM IV IM IV Sub-Q Oral IM IV Sub-Q

intravenous; Sub-Q subcutaneous.

Onset of Action (min) 1030 23 Within 15 23 Within 15 1530 1520 23 1520

Time to Peak Effect (min) 3060 30 60 30 6090 3060 1530 3060

Duration of Action (hr) 34 24 36 34 36 3 23 23 23

Mixed Agonist-Antagonist

Nalbuphine (Nubain)

Pentazocine (Talwin)


intramuscular; IV

antagonists, however, may produce more psychotropic effects (e.g., hallucinations, vivid dreams), and their maximal analgesic effect may not be as great as strong mu agonists.65 Consequently, these drugs are not used extensively, but they do offer an alternative to strongto-moderate opioid agonists in certain patients. A new addition to this category is buprenorphine (Buprenex). This drug partially activates mu receptors but is an antagonist at kappa receptors. Because of these selective effects, buprenorphine has been advocated not only as an analgesic, but also as a treatment for opioid dependence and withdrawal.26,84 The use of this drug in treating opioid addiction is discussed in more detail later in this chapter. Examples of mixed agonistantagonists include the following: butorphanol (Stadol) buprenorphine (Buprenex) nalbuphine (Nubain) pentazocine (Talwin)

tion. Other antagonists (e.g., naltrexone) are used in conjunction with behavioral therapy to maintain an opioid-free state in individuals recovering from opioid addiction. Hence, the primary agents used clinically as opioid antagonists are the following: nalmefene (Revex) naloxone (Narcan) naltrexone (ReVia)

Some opioid analgesics can be given orally, a preferred route of administration in terms of convenience and safety. Several of these enteral drugs also come in suppository form, permitting rectal administration if nausea and vomiting prohibit the oral route. Some opioidsincluding morphineare now available in sustained-release enteral preparations, thus allowing more prolonged effects and wider intervals between doses.6,12,50 Because of poor intestinal absorption or significant first-pass inactivation, other agents must be administered parenterally, usually through subcutaneous or intramuscular injection. Intravenous administration is also used sometimes, but must be done slowly and with caution. When the intravenous route is used, the narcotic is frequently diluted and infusion pumps are used to allow the slow, controlled administration of the drug. The intravenous route or other parenteral routes (epidural and intrathecal infusion) can also be used to administer opioids during patient-controlled analgesia; this concept is addressed in Chapter 17.

Antagonists. These drugs block all opioid receptors, with a particular affinity for the mu variety. Because of their antagonistic properties, these agents will not produce analgesia but will displace opioid agonists from the opioid receptors and block any further effects of the agonist molecules. Consequently, these drugs are used primarily to treat opioid overdoses and addiction. Certain opioid antagonists (e.g., nalmefene, naloxone) can rapidly (within 1 to 2 minutes) and dramatically reverse the respiratory depression that is usually the cause of death in excessive opioid inges-


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The feasibility of using other relatively new methods for administering opioids has also been investigated. For instance, transdermal patches have been developed to administer morphine, and other opioids such as fentanyl (Duragesic Patch), a potent and fast-acting opioid.12,68 The patch provides a convenient method for the steady, prolonged administration of these opioids into the systemic circulation. Transdermal opioid patches also avoid the direct administration of the drug to the gastrointestinal (GI) tract, and this fact may help reduce GI problems such as nausea and constipation.39 Iontophoresis techniques (i.e., the use of electric current to facilitate transdermal delivery) have also been advocated as a way to enhance transdermal opioid delivery to the systemic circulation.11 By varying the amount of electric current, iontophoresis may ultimately allow the patient to control the rate of transdermal administration of the opioid.10,76,78 Finally, certain opioids such as fentanyl can be administered systemically via lozenges or a lollipop that dissolves in the mouth (transmucosal delivery), or via nasal spray (intranasal administration).21,54 It will be interesting to see if these newer methods of administration will gain widespread acceptance in the future. Because of differing degrees of solubility, the distribution and subsequent onset of action of specific agents varies (see Table 142). Opioids are ultimately distributed throughout all tissues, and these agents probably exert their principal analgesic effects after they reach the CNS. Some opioid effects may also be mediated by peripheral receptors located at the site of painful inflammation (see Mechanism of Action below). Metabolic inactivation of these drugs takes place primarily in the liver, although some degree of metabolism also occurs in other tissues such as the kidneys, lungs, and CNS. The kidneys excrete the drug metabolite andto a lesser extentthe intact drug in the urine.

These areas include the periaqueductal gray region of the spinoreticular tract, medial thalamic nuclei, hypothalamus, limbic system, and several other areas.33,65,75 It is well accepted that opioids exert analgesic effects by inhibiting afferent pain transmission in ascending pain pathways. By acting at the key CNS sites listed above, opioids can inhibit painful impulses from being sent from the periphery to the brain. It is also believed that opioids exert some of their analgesic effects by activating descending pain pathways.27,33 That is, opioids can also affect efferent CNS pathways originating in higher centers (rostral medulla, locus ceruleus, midbrain periaqueductal gray area), and enhance the ability of these descending pathways to reduce painful sensations at the spinal cord level.65 This effect probably occurs because opioids inhibit interneurons that normally inhibit the ability of these descending pathways to moderate pain. This effect, known as disinhibition, ultimately activates the descending pathways by removing the inhibitory effect of these interneurons.33 By removing this inhibition, opioids allow these descending pathways to become more active and help control painful sensations. Hence, opioids seem to exert analgesic effects through their ability to decrease ascending (afferent) pain transmission, combined with their ability to activate descending (efferent) pathways that reduce pain.

Effect of Opioids on CNS Synapses

Opioids basically exert their analgesic effects by inhibiting synaptic transmission in key pain pathways in the spinal cord and brain. This inhibitory effect is mediated by opioid receptors that are located on both presynaptic and postsynaptic membranes of painmediating synapses (Fig. 142). In the spinal cord, for example, receptors are located on the presynaptic terminals of primary (first-order) nociceptive afferents, and when bound by opioids, they directly decrease the release of pain-mediating transmitters such as substance P.35,38 Opioid drug-receptor interactions also take place on the postsynaptic membrane of the secondary afferent neuronthat is, the second-order nociceptive afferent neuron in the spinal cord.19,33 When stimulated, these receptors also inhibit pain transmission by hyperpolarizing the postsynaptic neuron.19 Opioids therefore inhibit synaptic transmission by decreasing neurotransmitter release from the presynaptic terminal and by decreasing excitable (hyperpolarizing) postsynaptic neurons within key pain pathways in the spinal cord and brain. Again, these synaptic effects can either limit the transmission of painful stim-

Mechanism of Action
Effect of Opioids on the CNS
As discussed earlier, opioid receptors exist at specific locations throughout the CNS and possibly in peripheral nerve tissues as well. In the spinal cord, these receptors are concentrated on the neurons responsible for transmitting nociceptive input to higher (supraspinal) levels.33 Opioid receptors have likewise been identified in several locations of the brain that are associated with pain transmission and interpretation.

Chapter 14 Opioid Analgesics Opioids


Pain-mediating neurotransmitter

Decreased transmitter release from pre-synaptic neuron

Decreased excitability (hyperpolarization) of post-synaptic neuron

FIGURE 142 Schematic representation of how opioid analgesics may impair synaptic transmission in pain-mediating pathways. The drug binds to specific opioid receptors on the presynaptic and postsynaptic membranes.

uli in ascending pain pathways, or they can activate descending antinociceptive pathways by inhibiting interneurons that control these pathways. These effects are mediated through opioid receptors that are located on the membrane of these neurons, but are linked to the internal chemistry on the presynaptic and postsynaptic neurons through regulatory G proteins.1,65 As described in Chapter 4, regulatory G proteins act as an intermediate link between receptor activation and the intracellular effector mechanism that ultimately causes a change in cellular activity. In the case of opioid receptors, these G proteins interact with three primary cellular effectors: calcium channels, potassium channels, and the adenyl cyclase enzyme.27 At the presynaptic terminal, stimulation of opioid receptors activates G proteins that in turn inhibit the opening of calcium channels on the nerve membrane.65 Decreased calcium entry into the presynaptic terminal causes decreased neurotransmitter release because calcium influx mediates transmitter release at a chemical synapse. At the postsynaptic neuron, opioid receptors are linked via G proteins to potassium channels, and

activation of the receptor leads to an opening of these channels and a loss of potassium from the postsynaptic neuron.46 A relative loss of potassium from the postsynaptic neuron causes hyperpolarization because efflux of potassium (a cation) results in a relative increase in the negative intracellular electric potential. The postsynaptic neuron is therefore more difficult to excite because the interior of the cell is more negative. Finally, opioid receptors are linked via G proteins to the adenyl cyclase enzyme, and stimulation of the receptor leads to inhibition of this enzyme and decreased synthesis of cyclic adenosine monophosphate (cAMP). cAMP is an important second messenger that regulates neurotransmitter release from the presynaptic terminal and may also regulate the firing threshold of the postsynaptic neuron.27 Opioid-mediated inhibition of this second messenger therefore helps to explain how these drugs alter pain transmission. Hence, opioid drugs exert their analgesic effects by interacting with receptors that are linked to several intracellular effector mechanisms that ultimately lead to decreased synaptic transmission in specific pain pathways.


SECTION 4 Drugs Used to Treat Pain and Inflammation

Peripheral Effects of Opioids

Opioid receptors may exist outside the CNS, and some of the analgesic effects of opioid drugs may be mediated at peripheral sites.34,64 Opioid receptors have been identified on the distal (peripheral) ends of primary afferent (sensory) neurons.34,61 Binding opioid agents to these peripheral receptors will provide an analgesic effect by decreasing the excitability of these sensory neurons (Fig. 143). This idea is supported by the fact that endogenous opioids (endorphins, enkephalins) are often produced by leukocytes in peripheral tissues during certain types of painful inflammation, and that these endogenous substances seem to act locally on the peripheral sensory nerve terminals.9,45,61 Likewise, results from some studies in animals and humans suggest that exogenous opioids can be administered directly into peripheral tissues (e.g., injected into an inflamed joint) and that these agents exert analgesic effects even though the drug never reaches the CNS.27,65 Hence, evidence suggests that opioid receptors exist outside the CNS and opioid drugs may help produce analgesia at these peripheral sites. However, the clinical significance of these peripheral opioid effects remains to be fully determined. For instance, these receptors may play a role in mediating only certain types of pain, such as the pain associated with inflammation.59 Nonetheless, the fact that certain types of pain might be controlled by peripherally acting opioids has important pharmacologic implications. For instance, opioids that work exclusively in the periphery would not cause CNS-mediated side effects such as
(monocytes, macrophages, lymphocytes)

sedation, respiratory depression, and tolerance. Peripheral-acting opioids could be developed by creating lipophobic compounds that are unable to cross the blood-brain barrier.17,34 The use of these peripheralacting drugs remains fairly experimental at the present time, and additional clinical trials are needed to determine whether this becomes a viable means of treating certain types of pain.

Clinical Applications
Treatment of Pain
Opioid analgesics are most effective in treating moderate-to-severe pain that is more or less constant in duration. These drugs are not as effective in treating sharp, intermittent painalthough higher dosages will relieve this type of pain as well. Some examples of the clinical usage of opioid analgesics include the treatment of acute pain following surgery, trauma, and myocardial infarction, as well as the treatment of chronic pain in patients with conditions such as cancer. Because of the potential for serious side effects (see Problems and Adverse Effects below), these drugs should be used only when necessary, and the dose should be titrated according to the patients pain. Generally, oral administration of a mild-to-moderate opioid agonist should be used first, with stronger agonists being instituted orally and then parenterally if needed. In cases of chronic pain, pain control by nonopioid drugs should be attempted first. However, opioid analgesics should be instituted when the improvement in the quality of

(intraarticular injection)

Endogenous Peptides (endorphins, enkephalins, dynorphins)

Exogenous Opioids


Afferent Transmission


Opioid Receptors

Decreased excitability: decreased transmission of nociceptive input

FIGURE 143 Putative mechanism of opioid action on peripheral nerve terminals. See text for discussion.

Chapter 14 Opioid Analgesics


life offered to the patient with chronic pain clearly outweighs the potential risks of these drugs.28,51 Opioid analgesics often produce a rather unique form of analgesia as compared to the nonopioid agents. Opioids often alter the perception of pain rather than eliminating the painful sensation entirely. The patient may still be aware of the pain but it is no longer the primary focus of his or her attention. In a sense, the patient is no longer preoccupied by the pain. This type of analgesia is also often associated with euphoria and a sensation of floating. These sensations may be caused by the stimulation of specific types of opiate receptors within the limbic system (i.e., delta receptors). The route of opioid administration appears to be important in providing effective pain relief.2,7 Although the oral route is the easiest and most convenient, parenteral routes may be more effective in chronic or severe, intractable pain. In particular, administration directly into the epidural or intrathecal space has been suggested as being optimal in relieving pain following certain types of surgery, or in various types of acute or chronic pain.7,13,24,31,57,71 Since it is impractical to reinsert a needle every time the drug is needed, indwelling catheters are often implanted surgically so that the tip of the catheter lies in the epidural or intrathecal space. The free end of the catheter can be brought out through the patients skin and used to administer the opioid directly into the area surrounding the spinal cord. Alternatively, the catheter can be connected to some sort of a drug reservoir or pump that contains the opioid drug. Such devices can be located outside the patients body or implanted surgically beneath the patients skin (e.g., in the abdominal wall), and these pumps are programmed to deliver the drug at a fixed rate into the indwelling catheter.2 Although these programmable drug delivery systems do have some risks, they appear to be an effective way of treating patients with severe, chronic pain from malignant and nonmalignant sources.24 The effectiveness of opioid analgesics also appears to be influenced by the dosing schedule. The current consensus is that orally administered opioids are more effective when given at regularly scheduled intervals rather than when the patient feels the need for the drug.55,58 This may be because with regularly scheduled dosages, plasma concentrations may be maintained within a therapeutic range, rather than allowing the large plasma fluctuations that may occur if the drugs are given at sporadic intervals. On the other hand, it may simply be easier to control pain in its earlier stages before the pain can reach full intensity.58

Consistent with these hypotheses is the finding that continuous infusion of the opioid into the epidural or intrathecal space provides optimal pain relief postoperatively or in chronic, intractable pain.2,40,83 Continuous infusion is associated with certain side effects, especially nausea and constipation, as well as the potential for disruption of the drug delivery system.24,57,77 Problems with tolerance have also been reported during continuous administration,27 but it is somewhat controversial whether tolerance really develops when these drugs are used appropriately in the clinical management of pain (see section on Concepts of Addiction, Tolerance, and Physical Dependence). Hence, the benefit-to-risk ratio for continuous epidural or intrathecal infusion is often acceptable in patients with severe pain. This method of opioid administration continues to gain acceptance.24,57

Use of Opioids in PatientControlled Analgesia

Finally, some rather innovative techniques have been employed whereby the patient is able to control the delivery of the analgesic.5,20,60 These techniques are collectively known as patient-controlled analgesia (PCA) because the patient is able to periodically administer a specific dose of the drug (by pushing a button or some other device). PCA systems have some distinct advantages over conventional administration, and PCAs are often used following various types of surgery as well as in the treatment of certain types of chronic pain.5,13,60 The use of opioids and other drugs in PCA systems is discussed in Chapter 17.

Other Opioid Uses

Opioids have several other clinical applications. These agents can be used as an anesthetic premedication or as an adjunct in general anesthesia. Opioids are effective in cough suppression, and the short-term use of codeine and codeinelike agents in this regard is quite common. Opioid agonists decrease gastrointestinal motility and can be used to control cases of severe diarrhea. This effect is probably mediated indirectly through an effect on the CNS, as well as through a direct effect on the intestine. Finally, opioid agonists are used as an adjunct in cases of acute pulmonary edema. These drugs probably do not directly improve ventilatory capacity, but they do serve to reduce feelings of intense panic and anxiety associated with the


SECTION 4 Drugs Used to Treat Pain and Inflammation

dyspnea inherent to this disorder. Patients feel they can breathe more easily following opioid administration.

Problems and Adverse Effects

Opioid analgesics produce a number of central and peripheral side effects.32,48 Virtually all of these drugs have sedative properties and induce some degree of mental slowing and drowsiness. Patients taking opioids for the relief of pain may also become somewhat euphoric, although the manner and degree of such mood changes varies from individual to individual. One of the more potentially serious side effects is the respiratory depression often seen after narcotic administration.56 Within a few minutes after administration, these drugs cause the breathing rate to slow down, which can last for several hours. Although not usually a major problem when therapeutic doses are given to relatively healthy individuals, respiratory depression can be severe or even fatal in seriously ill patients, in patients with pre-existing pulmonary problems, or in cases of overdose. Some cardiovascular problems such as orthostatic hypotension may also occur immediately after opioids are administered, especially when parenteral routes are used. Finally, gastrointestinal distress in the form of nausea and vomiting is quite common with many of the narcotic analgesics. Because of their antiperistaltic action, these drugs can also cause constipation.48 Because this constipating effect can be quite severe, laxatives and stool softeners (see Chapter 27) can be used to prevent opioid-induced constipation in certain people, such as with patients who are at risk for fecal impaction (e.g., people with spinal cord injuries), or with people who are taking opioids for an extended period of time (e.g., patients receiving opioids for treatment of cancer-related pain).36,70

This concept of addiction is often separated from the physiologic changes that can accompany prolonged opioid use, namely tolerance and physical dependence. Tolerance is the need for more of a drug to achieve a given effect, and physical dependence is the onset of withdrawal symptoms if a drug is suddenly discontinued. Tolerance and physical dependence are also rather complex phenomena, and a complete discussion of the factors involved in producing these occurrences is not possible at this time. The primary characteristics of tolerance and physical dependence will be briefly discussed here as they relate to opioid usage.

Tolerance is defined as the need to progressively increase the dosage of a drug to achieve a therapeutic effect when the drug is used for prolonged periods.53 When used for the treatment of pain in some patients, the dosage of the opioid may need to be increased periodically to continue to provide adequate relief. The physiologic reasons for tolerance are complex and probably involve changes in the intracellular response to repeated stimulation of opioid receptors. Prolonged exposure to opioids can also cause a decrease in the number and sensitivity of the opioid receptorsa phenomenon known as receptor downregulation and desensitization (see Chapter 4).14,43,80 However, these changes in the quantity and sensitivity of opioid receptors do not seem to be the primary reasons for opioid tolerance.62 It seems more likely that tolerance is caused by changes in the intracellular effectors that are coupled to the opioid receptor, namely the G proteins and intracellular effector mechanisms.22,73 As described earlier, opioid receptors mediate their effects through regulatory G proteins that are linked to intracellular effectors, including the adenyl cyclase enzyme. Tolerance to opioid drugs, therefore, seems to be caused by long-term changes in G protein function and adenyl cyclase-induced synthesis of second messengers like cAMP.42,79 In a sense, tolerance occurs because the internal biochemistry of the cell has been blunted by repeated stimulation of the G protein-effector mechanisms. The physiologic changes that cause opioid tolerance typically follow a predictable time course. Tolerance begins after the first dose of the narcotic, but the need for increased amounts of the drug usually becomes obvious after 2 to 3 weeks of administration. Tolerance seems to last approximately 1 to 2 weeks after the drug is removed. This does not mean that the patient no longer has any desire for the drug, but that

Concepts of Addiction, Tolerance, and Physical Dependence

When used inappropriately, opioid drugs can produce addiction. The term addiction typically refers to situations in which an individual repeatedly seeks out and ingests certain substances for mood-altering and pleasurable experiences, such as the heroin addict who takes the drug illicitly to achieve an opioid high. In this sense, addiction is a very complex phenomenon that has strong psychologic implications regarding why certain chemicals cause this behavior in certain people.

Chapter 14 Opioid Analgesics


the patient will again respond to the initial dosage after 14 days or so. Other factors may influence the individuals desire for the drug long after any physiologic effects have disappeared (see Physical Dependence).

Physical Dependence
Physical dependence is usually defined as the onset of withdrawal symptoms when the drug is abruptly removed. Withdrawal syndrome from opioid dependence is associated with a number of obvious and unpleasant symptoms (Table 143). In severe dependence, withdrawal symptoms become evident within 6 to 10 hours after the last dose of the drug, and symptoms reach their peak in the second or third day after the drug has been stopped. Withdrawal symptoms last approximately 5 days. This does not necessarily mean that the individual no longer desires the drug, only that the physical symptoms of withdrawal have ceased. Indeed, an addict may continue to crave the drug after months or years of abstinence. Physical dependence must therefore be differentiated from the more intangible concepts of addiction and psychologic dependence. Psychologic dependence seems to be related to pleasurable changes in mood and behavior evoked by the drug. The individual is motivated to continually reproduce these pleasurable sensations because of the feelings of well-being, relaxation, and so on. Psychologic dependence seems to create the drug-seeking behavior that causes the addict to relapse into use of the drug long after the physiologic effects have disappeared.

Tolerance and Dependence During Therapeutic Opioid Use

Although tolerance and dependence can occur whenever opioid drugs are used indiscriminately for pro-

Table 143


Runny nose Shivering Sneezing Stomach cramps Sweating Tachycardia Uncontrollable yawning Weakness/fatigue

longed periods, there is some debate as to whether these phenomena must always accompany the therapeutic use of opioid drugs for the treatment of chronic pain. There is growing evidence that the risk of tolerance and dependence is actually very low when opioid drugs are used appropriately to treat chronic pain.8,18 For example, there appear to be relatively few problems with long-term opioid use when these drugs are administered to treat pain in patients who do not have a history of substance abuse, who adhere to the prescribed opioid regimen, and who have pain from physiological rather than psychological causes.18,52 Some experts also feel that tolerance and physical dependence will not occur if the dosage is carefully adjusted to meet the patients needs.4,8 It is believed that when the opioid dose exactly matches the patients need for pain control, there is no excess drug to stimulate the drug-seeking behavior commonly associated with opioid addiction. The opioid is essentially absorbed by the patients pain. Of course, patients with chronic pain may still need to have the dosage increased periodically. This observation would be explained by the fact that the pain has increased because the patients condition has worsened (e.g., the cancer has increased) rather than the idea that the patient developed pharmacologic tolerance to the drug.28,51 Thus, many practitioners feel that problems with addiction, tolerance, and dependence are minimized when opioid drugs are used therapeutically. These agents are essentially being used for a specific reasonthe treatment of painrather than for the pleasure-seeking purpose associated with the recreational use of these drugs. These drugs must, of course, be used carefully and with strict regard to using the lowest effective dose. Hence, there is consensus that opioids are very effective and important analgesic agents and should be used under appropriate therapeutic conditions without excessive fear of the patient developing addiction or becoming especially tolerant to the drugs effects.4,18

Pharmacological Treatment of Opioid Addiction

The inappropriate or illegal use and abuse of narcotics such as heroin is a major problem in many countries. Hence, various strategies have been employed to treat people who are addicted to heroin and other opioids. Methadone is the primary pharmacological intervention used to treat opioid addiction. Methadone is a strong opioid agonist, similar in potency and efficacy to morphine. While giving an opioid to treat an opi-

Body aches Diarrhea Fever Gooseflesh Insomnia Irritability Loss of appetite Nausea/vomiting


SECTION 4 Drugs Used to Treat Pain and Inflammation

oid addiction may at first appear odd, methadone offers several advantages, such as milder withdrawal symptoms. Methadone is essentially substituted for the abused opioid (e.g., heroin), and is then slowly withdrawn as various methods of counseling are employed to discourage further drug abuse.3,74 Use of methadone, however, remains controversial because of the rather low success rate of this intervention and the tendency for many subjects to relapse and return to opioid abuse.37 Still, methadone maintenance programs are more successful than using no pharmacological intervention,47 and methadone remains the primary drug strategy used to treat opioid addiction.74 Recently, buprenorphine has been advocated as an alternative pharmacological method for treating opioid

addiction.26,84 As indicated earlier, buprenorphine is a mixed agonist-antagonist that partially stimulates mu opioid receptors while acting as a strong antagonist at kappa opioid receptors. By weakly stimulating the mu receptors, this drug can sustain the opioid effects and prevent sudden withdrawal. At the same time, buprenorphine can block kappa receptors, thereby affecting some of the cellular changes that seem to promote opioid addiction. Hence, this drug offers another method of substituting a therapeutic agent for the abused opioid, with the ultimate goal being to eventually wean the patient from all opioid drugs.16 Hence, efforts continue to provide more effective pharmacological and nonpharmacological interventions for treating opioid addiction.41 As more infor-

Special Concerns in Rehabilitation Patients

Physical therapists will encounter the use of opioid analgesics in patients requiring acute pain relief (following surgery, trauma, etc.) and chronic analgesia (for patients with terminal cancer and other types of severe chronic pain). The usual side effects of sedation and gastrointestinal discomfort may be bothersome during some of the therapy sessions. However, the relief of pain afforded by these drugs may be helpful in allowing a relatively more vigorous and comprehensive rehabilitation regimen. The benefits of pain relief usually outweigh side effects such as sedation. Scheduling therapy when these drugs reach their peak effects may be advantageous (see Table 142). One side effect that should be taken into account during therapy is the tendency of these drugs to produce respiratory depression. Opioids tend to make the medullary chemoreceptors less responsive to carbon dioxide, thus slowing down the respiratory rate and inducing a relative hypoxia and hypercapnia.27 This fact should be considered if any exercise is instituted as part of the rehabilitation program. The respiratory response to this exercise may be blunted. The tendency for these drugs to produce constipation is another side effect that could have important implications for patients receiving physical rehabilitation. Opioid-induced constipation is especially problematic in patients with spinal cord injuries or other conditions that decrease gastrointestinal motility. In such patients, opioids are often administered along with laxatives and GI stimulants (see Chapter 27) to minimize the constipating effects and risk of fecal impaction. Therapists should therefore be aware of these constipating effects and help educate patients and their families so that these effects do not result in serious problems. Therapists may also be working with patients who are experiencing withdrawal symptoms from opioid drugs. Such patients may be in the process of being weaned off the therapeutic use of these agents, or they may be heroin addicts who have been hospitalized for other reasons (e.g., trauma, surgery). If not on some type of methadone maintenance, the addict may be experiencing a wide variety of physical symptoms including diffuse muscle aches. The therapist should be aware that these aches and pains may be caused by opioid withdrawal rather than an actual somatic disorder. Therapists may, however, help the patient cope with opioid withdrawal by using various physical agents (heat, electrotherapy) and manual techniques (massage, relaxation techniques) to alleviate these somatic symptoms.

Chapter 14 Opioid Analgesics


Opioid Analgesics
Brief History. N.P., a 45-year-old woman, was involved in an automobile accident approximately 6 months ago. She received multiple contusions from the accident, but no major injuries were sustained. Two months later, she began to develop pain in the right shoulder. This pain progressively increased, and she was treated for bursitis using anti-inflammatory drugs. Her shoulder motion became progressively more limited; however, any movement of her glenohumeral joint caused rather severe pain. She was reevaluated and a diagnosis of adhesive capsulitis was made. The patient was admitted to the hospital, and while she was under general anesthesia, a closed manipulation of the shoulder was performed. When the patient recovered from the anesthesia, meperidine (Demerol) was prescribed for pain relief. This drug was given orally at a dosage of 75 mg every 4 hours. Physical therapy was also initiated the afternoon following the closed manipulation. Passive range-of-motion exercises were used to maintain the increased joint mobility achieved during the manipulative procedure. Relevance to Therapy/Clinical Decision. The therapist arranged the treatment schedule so that the meperidine was reaching peak effects during the therapy session. The patient was seen approximately 1 hour following the oral administration of the drug. The initial session was scheduled at the patients bedside because the patient was still woozy from the anesthesia. On the following day, therapy was continued in the physical therapy department. However, the patient was brought to the department on a stretcher to prevent an episode of dizziness brought on by orthostatic hypotension. On the third day, the patients medication was changed to oxycodone (OxyContin), a mild-to-moderate opioid agonist. By this time, the patient was being transported to physical therapy in a wheelchair, and the therapy session also included active exercise. The patient was discharged on the fourth day after the manipulative procedure. She continued to attend therapy as an outpatient, and full function of her right shoulder was ultimately restored.

mation is gained about the cellular and subcellular mechanisms that cause addiction, we may see other agents being used to specifically treat these changes and thereby offer a more effective way to prevent and treat opioid abuse.

Opioid analgesics represent some of the most effective methods of treating moderate-to-severe pain. When used properly, these agents can alleviate acute and chronic pain in a variety of situations. The use of these

drugs is sometimes tempered with their tendency to produce tolerance and physical dependence, but their potential for abuse seems relatively low when these drugs are used appropriately to treat pain. Opioid drugs therefore represent the most effective pharmacologic means of helping patients deal with acute and chronic pain. The analgesic properties of these drugs often provide a substantial benefit in patients involved in rehabilitation. Physical therapists should be aware of some of the side effects, such as sedation and respiratory depression, and should be cognizant of the impact of these effects during the rehabilitation session.

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7. Block BM, Liu SS, Rowlingson AJ, et al. Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA. 2003;290:24552463. 8. Bloodworth D. Issues in opioid management. Am J Phys Med Rehabil. 2005;84(suppl 3):S42S55. 9. Brack A, Rittner HL, Machelska H, et al. Endogenous peripheral antinociception in early inflammation is not limited by the number of opioid-containing leukocytes but by opioid receptor expression. Pain. 2004;108: 6775. 10. Chelly JE, Grass J, Houseman TW, et al. The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multicenter, placebo-controlled trial. Anesth Analg. 2004; 98:427433. 11. Ciccone CD. Iontophoresis. In: Robinson AJ, SnyderMackler L eds. Clinical Electrophysiology 2nd ed. Baltimore: Lippincott Williams & Wilkins, 1994. 12. Clark AJ, Ahmedzai SH, Allan LG, et al. Efficacy and safety of transdermal fentanyl and sustained-release oral morphine in patients with cancer and chronic non-cancer pain. Curr Med Res Opin. 2004;20: 14191428. 13. Colwell CW, Jr. The use of the pain pump and patient-controlled analgesia in joint reconstruction. Am J Orthop. 2004;33(suppl 5):1012. 14. Connor M, Osborne PB, Christie MJ. Mu-opioid receptor desensitization: is morphine different? Br J Pharmacol. 2004;143:685696. 15. Contet C, Kieffer BL, Befort K. Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol. 2004; 14:370378. 16. Davids E, Gastpar M. Buprenorphine in the treatment of opioid dependence. Eur Neuropsychopharmacol. 2004; 14:209216. 17. DeHaven-Hudkins DL, Dolle RE. Peripherally restricted opioid agonists as novel analgesic agents. Curr Pharm Des. 2004;10:743757. 18. Dews TE, Mekhail N. Safe use of opioids in chronic noncancer pain. Cleve Clin J Med. 2004;71:897904. 19. Eckert WA 3rd, Light AR. Hyperpolarization of substantia gelatinosa neurons evoked by mu-, kappa-, delta 1-, and delta 2-selective opioids. J Pain. 2002; 3:115125. 20. Evans E, Turley N, Robinson N, Clancy M. Randomised controlled trial of patient controlled analgesia compared with nurse delivered analgesia in an emergency department. Emerg Med J. 2005;22:2529. 21. Finn J, Wright J, Fong J, et al. A randomised crossover trial of patient controlled intranasal fentanyl and oral morphine for procedural wound care in adult patients with burns. Burns. 2004;30:262268. 22. Gainetdinov RR, Premont RT, Bohn LM, et al. Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci. 2004;27: 107144. 23. Gein SV, Simonenko TA, Tendryakova SP. The effects of rotation stress on measures of immunity. The role of opiate receptors. Neurosci Behav Physiol. 2004;34: 935938.

Chapter 14 Opioid Analgesics 44. Lugo RA, Kern SE. Clinical pharmacokinetics of morphine. J Pain Palliat Care Pharmacother. 2002; 16:518. 45. Machelska H, Schopohl JK, Mousa SA, et al. Different mechanisms of intrinsic pain inhibition in early and late inflammation. J Neuroimmunol. 2003;141:3039. 46. Marker CL, Lujan R, Loh HH, Wickman K. Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of muand delta- but not kappa-opioids. J Neurosci. 2005;25: 35513559. 47. Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2003;CD002209. 48. McNicol E, Horowicz-Mehler N, Fisk RA, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain. 2003;4:231256. 49. Molina PE. Endogenous opioid analgesia in hemorrhagic shock. J Trauma. 2003;54(suppl 5):S126S132. 50. Morales ME, Gallardo Lara V, Calpena AC, et al. Comparative study of morphine diffusion from sustained release polymeric suspensions. J Control Release. 2004;95:7581. 51. Moynihan TJ. Use of opioids in the treatment of severe pain in terminally ill patientsdying should not be painful. Mayo Clin Proc. 2003;78:1397401. Review [erratum in Mayo Clin Proc. 2003;78:1579]. 52. Olsen Y, Daumit GL. Opioid prescribing for chronic nonmalignant pain in primary care: challenges and solutions. Adv Psychosom Med. 2004;25:138150. 53. Ossipov MH, Lai J, King T, et al. Antinociceptive and nociceptive actions of opioids. J Neurobiol. 2004;61: 126148. 54. Paech MJ, Lim CB, Banks SL, Rucklidge MW, Doherty DA. A new formulation of nasal fentanyl spray for postoperative analgesia: a pilot study. Anaesthesia. 2003;58:740744. 55. Patterson DR, Ptacek JT, Carrougher G, et al. The 2002 Lindberg Award. PRN vs regularly scheduled opioid analgesics in pediatric burn patients. J Burn Care Rehabil. 2002;23:424430. 56. Pattinson KT, Bowes M, Wise RG, et al. Evaluation of a non-invasive method of assessing opioid induced respiratory depression. Anaesthesia. 2005;60:426432. 57. Penn RD. Intrathecal medication delivery. Neurosurg Clin N Am. 2003;14:381387. 58. Phero JC, Becker DE, Dionne RA. Contemporary trends in acute pain management. Curr Opin Otolaryngol Head Neck Surg. 2004;12:209216. 59. Pol O, Puig MM. Expression of opioid receptors during peripheral inflammation. Curr Top Med Chem. 2004;4:5161. 60. Prakash S, Fatima T, Pawar M. Patient-controlled analgesia with fentanyl for burn dressing changes. Anesth Analg. 2004;99:552555. 61. Puehler W, Stein C. Controlling pain by influencing neurogenic pathways. Rheum Dis Clin North Am. 2005; 31:103113, ix.


62. Raith K, Hochhaus G. Drugs used in the treatment of opioid tolerance and physical dependence: a review. Int J Clin Pharmacol Ther. 2004;42:191203. 63. Rasmussen NA, Farr LA. Effects of morphine and time of day on pain and beta-endorphin. Biol Res Nurs. 2003;5:105116. 64. Riviere PJ. Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol. 2004;141:13311334. 65. Schumacher MA, Basbaum AI, Way WL. Opioid analgesics and antagonists. In: Katzung BG ed. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw Hill; 2004. 66. Shavali S, Ho B, Govitrapong P, et al. Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Res Bull. 2005;64:471479. 67. Sher L. The role of endogenous opioids in the placebo effect in post-traumatic stress disorder. Forsch Komplementarmed Klass Naturheilkd. 2004;11:354359. 68. Skaer TL. Practice guidelines for transdermal opioids in malignant pain. Drugs. 2004;64:26292638. 69. Smith AP, Lee NM. Opioid receptor interactions: local and nonlocal, symmetric and asymmetric, physical and functional. Life Sci. 2003;73:18731893. 70. Tamayo AC, Diaz-Zuluaga PA. Management of opioid-induced bowel dysfunction in cancer patients. Support Care Cancer. 2004;12:613618. 71. Tobias JD. A review of intrathecal and epidural analgesia after spinal surgery in children. Anesth Analg. 2004; 98:956965. 72. Tordjman S, Carlier M, Cohen D, et al. Aggression and the three opioid families (endorphins, enkephalins, and dynorphins) in mice. Behav Genet. 2003;33: 529536. 73. Tso PH, Wong YH. Molecular basis of opioid dependence: role of signal regulation by G-proteins. Clin Exp Pharmacol Physiol. 2003;30:307316. 74. Uchtenhagen A. Substitution management in opioid dependence. J Neural Transm Suppl. 2003:3360. 75. Vaughan CW, Bagley EE, Drew GM, et al. Cellular actions of opioids on periaqueductal grey neurons from C57B16/J mice and mutant mice lacking MOR-1. Br J Pharmacol. 2003;139:362367. 76. Viscusi ER. Emerging techniques for postoperative analgesia in orthopedic surgery. Am J Orthop. 2004; 33(suppl 5):1316. 77. Viscusi ER. Emerging techniques in the treatment of postoperative pain. Am J Health Syst Pharm. 2004;61 (suppl 1):S11S14. 78. Viscusi ER, Reynolds L, Chung F, et al. Patientcontrolled transdermal fentanyl hydrochloride vs intravenous morphine pump for postoperative pain: a randomized controlled trial. JAMA. 2004;291: 13331341. 79. von Zastrow M. A cell biologists perspective on physiological adaptation to opiate drugs. Neuropharmacology. 2004;47(suppl 1):286292. 80. von Zastrow M, Svingos A, Haberstock-Debic H, Evans C. Regulated endocytosis of opioid receptors:


SECTION 4 Drugs Used to Treat Pain and Inflammation 83. Werawatganon T, Charuluxanun S. Patient controlled intravenous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery. Cochrane Database Syst Rev. 2005;CD004088. 84. Wesson DR. Buprenorphine in the treatment of opiate dependence: its pharmacology and social context of use in the U.S. J Psychoactive Drugs. 2004;suppl 2:119128. 85. Zadina JE. Isolation and distribution of endomorphins in the central nervous system. Jpn J Pharmacol. 2002; 89:203208.

cellular mechanisms and proposed roles in physiological adaptation to opiate drugs. Curr Opin Neurobiol. 2003;13:348353. 81. Vrinten DH, Gispen WH, Kalkman CJ, Adan RA. Interaction between the spinal melanocortin and opioid systems in a rat model of neuropathic pain. Anesthesiology. 2003;99:449454. 82. Wei LN, Law PY, Loh HH. Post-transcriptional regulation of opioid receptors in the nervous system. Front Biosci. 2004;9:16651679.



Nonsteroidal Anti-Inflammatory Drugs

This chapter discusses a chemically diverse group of substances that exert several distinct pharmacologic properties. These properties include (1) the ability to decrease inflammation, (2) the ability to relieve mild-to-moderate pain (analgesia), (3) the ability to decrease elevated body temperature associated with fever (antipyresis), and (4) the ability to decrease blood clotting by inhibiting platelet aggregation (anticoagulation). These drugs are commonly referred to as nonsteroidal anti-inflammatory drugs (NSAIDs) to distinguish them from the glucocorticoids (i.e., the other main group of drugs used to treat inflammation). Obviously, the term NSAID does not fully describe these agents pharmacologic actions; a more inclusive terminology should also mention the analgesic, antipyretic, and anticoagulant effects. However, these drugs are typically referred to as NSAIDs, and this terminology is used throughout this chapter. Because of their analgesic and anti-inflammatory effects, patients receiving physical therapy often take NSAIDs for any number of problems. These drugs are a mainstay in the treatment of many types of mild-tomoderate pain, and NSAIDs are especially useful in treating pain and inflammation occurring in acute and chronic musculoskeletal disorders. Other patients are given NSAIDs to treat fever or to prevent excessive blood clotting. Consequently, physical therapists and other rehabilitation specialists will notice that these drugs are used quite frequently in their patient population, with the specific therapeutic goal related to each patients individual needs.

Aspirin and Other NSAIDs: General Aspects

The best representative of an NSAID is aspirin (acetylsalicylic acid; Fig. 151). Newer NSAIDs are usually compared to aspirin in terms of efficacy and safety. Acetaminophen is another agent that is similar to aspirin and other NSAIDs in its ability to decrease pain and fever. Acetaminophen, however, is not considered an NSAID because it lacks anti-inflammatory and anticoagulant properties. For a discussion of the comparative effects of aspirin, newer NSAIDs, and acetaminophen, see Comparison of Aspirin with Other NSAIDs. For years, it was a mystery how a drug like aspirin could exert such a diverse range of therapeutic effects; COOH OCOCH3

Aspirin (acetylsalicylic acid)

FIGURE 151 Structure of aspirin.



SECTION 4 Drugs Used to Treat Pain and Inflammation

that is, how could one drug influence so many different systemseffectively alleviating pain and inflammation, decreasing fever, and even affecting blood clotting? This issue was essentially resolved in the early 1970s, when aspirin was found to inhibit the synthesis of a group of endogenous compounds known collectively as the prostaglandins. We now know that aspirin and the other NSAIDs exert most, if not all, of their therapeutic effects by interfering with the biosynthesis of prostaglandins and other related compounds.37,91,103 To understand the way in which these drugs work, a brief discussion of prostaglandins and similar endogenously produced substances is presented.

identified as being able to produce prostaglandins. These compounds appear to be hormones that act locally to help regulate cell function under normal and pathologic conditions. Other biologically active compounds known as the thromboxanes and leukotrienes are derived from the same precursor as the prostaglandins.2,73,80 Together, the prostaglandins, thromboxanes, and leukotrienes are often referred to as eicosanoids because they all are derived from 20carbon fatty acids that contain several double bonds.66,73,88 (The term eicosanoid is derived from eicosa, meaning 20-carbon, and enoic, meaning containing double bonds.)

Eicosanoid Biosynthesis

Prostaglandins, Thromboxanes, and Leukotrienes

Prostaglandins are a group of lipidlike compounds that exhibit a wide range of physiologic activities.37,48,68 With the exception of the red blood cell, virtually every type of living cell in the human body has been

The biosynthetic pathway of prostaglandins and other eicosanoids is outlined in Figure 152. Basically, these compounds are derived from a 20-carbon essential fatty acid. In humans, this fatty acid is usually arachidonic acid,68,73 which is ingested in the diet and stored as a phospholipid in the cell membrane. Thus, the cell has an abundant and easily accessible supply of this

Membrane Phospholipids

Arachadonic Acid






LTC4 PGI2 LTD4 LTE4 LTF4 6-Keto PGF1 PGE2 PGD2 PGF2 TXB2 leukotriene. TXA2

FIGURE 152 Eicosanoid biosynthesis. PG

prostaglandin; TX

thromboxane; LT

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precursor. When needed, arachidonic acid is cleaved from the cell membrane by a phospholipase enzyme (i.e., phospholipase A2). The 20-carbon fatty acid can then be metabolized by several enzyme systems to generate a variety of biologically active compounds. One of the primary enzyme systems involves the cyclooxygenase (COX) enzyme, and a second system involves the lipoxygenase (LOX) enzyme. The prostaglandins and thromboxanes are ultimately synthesized from the cyclooxygenase pathway, and the leukotrienes come from the lipoxygenase system (see Fig. 152).73 Exactly which pathway is used in any particular cell depends on the type and quantity of enzymes in that cell, as well as its physiologic status. The end products within a given pathway (i.e., exactly which prostaglandins, thromboxanes, or leukotrienes will be formed) also depend on the individual cell. Any drug inhibiting one of these enzymes will also inhibit the formation of all of the subsequent products of that particular pathway. A drug that blocks the cyclooxygenase will essentially eliminate all prostaglandin and thromboxane synthesis in that cell. As this chapter will later discuss, aspirin and the other NSAIDs are cyclooxygenase inhibitors, which is the way that these drugs exert their therapeutic effects (see Mechanism of NSAID Action: Inhibition of Prostaglandin and Thromboxane Synthesis). Aspirin and other NSAIDs do not inhibit the lipoxygenase enzyme and thus do not appreciably decrease leukotriene synthesis.73 Like the prostaglandins, leukotrienes are pro-inflammatory, but leukotrienes seem to be more important in mediating airway inflammation in conditions such as asthma and allergic rhinitis (see Chapter 26).2,20 Drugs have therefore been developed to reduce leukotriene-mediated inflammation by either inhibiting the lipoxygenase enzyme (e.g., zileuton) or by blocking leukotriene receptors on respiratory tissues (e.g., montelukast and zafirlukast).20,83 These antileukotriene drugs will be discussed in more detail in Chapter 26. The remainder of this chapter will focus on drugs that inhibit prostaglandin and thromboxane production by selectively inhibiting the cyclooxygenase enzyme.

Role of Eicosanoids in Health and Disease

The prostaglandins, thromboxanes, and leukotrienes have been shown to have a variety of effects on virtually every major physiologic system. Studies have indicated that these compounds can influence cardio-

vascular, respiratory, renal, gastrointestinal, nervous, and reproductive function.48,73 The biologic effects of the various eicosanoids cannot be generalized. Different classes of eicosanoids, and even different members within the same class, may exert various effects on the same system. For instance, certain prostaglandins such as the PGIs and PGEs tend to produce vasodilation in most vascular beds, whereas other prostaglandins (e.g., PGF2 ) and the thromboxanes are often vasoconstrictors.30,73,96 Some of the major effects of the eicosanoids are summarized in Table 151. All of the effects of different prostaglandins, thromboxanes, and leukotrienes on various systems in the body cannot be reviewed in this chapter; this issue has been reviewed extensively elsewhere.13,48,50,73,88 Of greater interest is the role of prostaglandins and related substances in pathologic conditions. In general, cells that are subjected to various types of trauma or disturbances in homeostasis tend to increase the production of prostaglandins.50,73 This finding suggests that prostaglandins and other eicosanoids may be important in the protective response to cellular injury. In addition, prostaglandins are important in mediating some of the painful effects of injury and inflammation, as well as the symptoms of other pathologic conditions. Some of the better-documented conditions associated with excessive prostaglandin synthesis are listed here. Inflammation. Increased prostaglandin synthesis is usually detected at the site of local inflammation.21,66,73,101 Certain prostaglandins, such as PGE2, are thought to help mediate the local erythema and edema associated with inflammation by increasing local blood flow, increasing capillary permeability, and potentiating the permeability effects of histamine and bradykinin.13,73 Leukotrienes, particularly LTB4, also contribute to the inflammatory response by increasing vascular permeability, and LTB4 has a potent chemotactic effect on polymorphonuclear leukocytes.73,80 Pain. Prostaglandins appear to help mediate painful stimuli in a variety of conditions (including inflammation). The compounds do not usually produce pain directly but are believed to increase the sensitivity of pain receptors to mechanical pressure and the effects of other pain-producing substances such as bradykinin.73 Fever. Prostaglandins appear to be pyretogenic; that is, they help produce the elevated body temperature during fever.55 Although the details are somewhat unclear, prostaglandins produced in hypothalamic blood vessels may promote fever by altering the thermoregulatory set-point within the hypothalamus so


SECTION 4 Drugs Used to Treat Pain and Inflammation

Table 151

Airway Smooth Muscle Gastrointestinal Smooth Muscle Gastrointestinal Secretions Decrease Decrease Uterine Muscle (Nonpregnant) Relaxation Relaxation Platelet Aggregation Variable

Class PGAs PGEs

Vascular Smooth Muscle Vasodilation Vasodilation

Bronchodila- Contraction tion Relaxation


Vasodilation Variable




Bronchocon- Contraction striction


Vasoconstric- Bronchocon- tion striction Vasoconstric- Bronchocon- Contraction tion striction

prostaglandins, TXs thromboxanes, LTs leukotrienes.



that body temperature is maintained at a higher level.10 Alternatively, prostaglandin production may promote fever by stimulating vagal afferent neurons that originate peripherally near the diaphragm.10 Regardless of their exact mechanism, prostaglandins clearly play a role in promoting fever associated with systemic infection and other pyretogenic disorders.55 Dysmenorrhea. The painful cramps that accompany menstruation in some women have been attributed at least in part to increased prostaglandin production in the endometrium of the uterus.56,70 Thrombus Formation. The thromboxanes, especially TXA2, cause platelet aggregations that result in blood clot formation.73 It is unclear whether excessive thrombus formation (as in deep vein thrombosis or coronary artery occlusion) is initiated by abnormal thromboxane production. Certainly, inhibition of thromboxane synthesis will help prevent plateletinduced thrombus formation in individuals who are prone to specific types of excessive blood clotting.84 Other Pathologies. Because of their many varied physiologic effects, the eicosanoids are involved in a number of other pathologic conditions. Prostaglandins have been implicated in cardiovascular disorders (hypertension), neoplasms (colon cancer), respiratory dysfunction (asthma), neurologic disorders (multiple

sclerosis, allergic encephalomyelitis, affective disorders), endocrine dysfunction (Bartter syndrome, diabetes mellitus), and a variety of other problems. 7,17,40, 77,93,110 The exact role of prostaglandins and the other eicosanoids in various diseases continues to be evaluated, and the role of these compounds in health and disease has become clearer with ongoing research.

Mechanism of NSAID Action: Inhibition of Prostaglandin and Thromboxane Synthesis

Aspirin and the other NSAIDs are all potent inhibitors of the cyclooxygenase enzyme.37,84,91,103 Because cyclooxygenase represents the first step in the synthesis of prostaglandins and thromboxanes, drugs that inhibit this enzyme in any given cell will block the production of all prostaglandins and thromboxanes in that cell. Considering that prostaglandins and thromboxanes are implicated in producing pain, inflammation, fever, and excessive blood clotting, virtually all of the therapeutic effects of aspirin and similar drugs can be explained by their ability to inhibit the synthesis of these two eicosanoid classes.103

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The cyclooxygenase or COX enzyme system is therefore the key site of NSAID action within the cell. It is now realized, however, that there are at least two primary subtypes (isozymes) of the COX enzyme: COX-1 and COX-2.24,37,103 The COX-1 enzyme is a normal constituent in certain cells, and prostaglandins synthesized by COX-1 are typically responsible for mediating normal cell activity and maintaining homeostasis. For example, COX-1 enzymes located in the stomach mucosa synthesize prostaglandins that help protect the stomach lining from gastric acid, and COX-1 enzymes in the kidneys produce beneficial prostaglandins that help maintain renal function, especially when kidney function is compromised.27,46,95 COX-1 is also the enzyme responsible for synthesizing prostaglandins and thromboxanes regulating normal platelet activity.73 The COX-2 enzyme, however, seems to be produced primarily in injured cells; that is, other chemical mediators (cytokines, growth factors) induce the injured cell to synthesize the COX-2 enzyme, and this enzyme then produces prostaglandins that mediate pain and other aspects of the inflammatory response.19,61,84 There is also considerable evidence that the COX-2 form is responsible for producing prostaglandins in other pathological conditions such as colorectal cancer.62,100 The roles of COX-1 and COX-2 enzymes therefore seem quite different. The COX-1 enzyme is a normal cell component that synthesizes prostaglandins to help regulate and maintain cell activity. COX-2 represents an emergency enzyme that often synthesizes prostaglandins in response to cell injury (i.e., pain and inflammation). This difference has important implications for how NSAIDs exert their therapeutic effects and side effects. Aspirin and most of the traditional NSAIDs are nonselectivethey inhibit both the COX-1 and COX-2 enzymes. These nonselective NSAIDs therefore cause primary beneficial effects (decreased pain and inflammation) by inhibiting the COX-2 enzyme. Because these drugs also inhibit the COX-1 enzyme, they also decrease the production of the beneficial and protective prostaglandins. It is the loss of these beneficial prostaglandins that accounts for the primary side effects of the NSAIDs; that is, loss of protective prostaglandins in the stomach and kidneys result in gastric damage and decreased renal function, respectively. It follows that drugs selectively inhibiting the COX-2 enzyme offer certain advantages over aspirin and nonselective NSAIDs. Selective COX-2 inhibitors should decrease the production of prostaglandins that

mediate pain and inflammation while sparing the synthesis of protective prostaglandins that are synthesized by COX-1. Such COX-2 selective drugs are currently available, and their pharmacology is addressed later in this chapter.

Aspirin: Prototypical NSAID

Acetylsalicylic acid, or aspirin, as it is commonly known (see Fig. 151), represents the major form of a group of drugs known as the salicylates. Other salicylates (sodium salicylate, choline salicylate) are used clinically, but aspirin is the most frequently used and appears to have the widest range of therapeutic effects. Because aspirin has been used clinically for more than 100 years, is inexpensive, and is readily available without prescription, many individuals may be under the impression that this drug is only a marginally effective therapeutic agent. On the contrary, aspirin is a very powerful and effective drug that should be considered a major medicine.84 As discussed previously, aspirin is a potent inhibitor of all cyclooxygenase activity (COX-1 and COX-2), and thus it has the potential to affect a number of conditions involving excessive prostaglandin and thromboxane production. Aspirin is the oldest and most widely used NSAID, and other NSAIDs are compared with aspirin in terms of efficacy and safety. Hence, this discussion focuses primarily on the clinical applications of aspirin and the problems typically associated with aspirin. For the most part, clinical use and problems can also be applied to most nonaspirin NSAIDs. The major similarities and differences between aspirin and the other NSAIDs are discussed in Comparison of Aspirin with Other NSAIDs.

Clinical Applications of Aspirinlike Drugs

Treatment of Pain and Inflammation
Aspirin and other NSAIDs are effective in treating mild-to-moderate pain of various origins, including headache, toothache, and diffuse muscular aches and soreness. Aspirin appears to be especially useful in treating pain and inflammation in musculoskeletal and joint disorders.71,87,89 The safe and effective use of aspirin in both rheumatoid arthritis and osteoarthritis is well documented (see Chapter 16).53,66,84 Aspirin is also recommended for treating the pain and cramping associated with primary dysmenorrhea.70


SECTION 4 Drugs Used to Treat Pain and Inflammation

Aspirin and aspirinlike drugs are also used to manage pain following certain types of surgery, including arthroscopic surgery.15,16 These drugs can serve as the primary analgesic following other types of minor or intermediate surgeries, and they can be used after extensive surgery to decrease the need for high doses of other drugs such as opioids.12,69 Ketorolac tromethamine (Toradol), for example, is a relatively new NSAID that has shown exceptional promise in treating postoperative pain. This drug can be given orally or by intramuscular injection, and it is reported to provide analgesic effects similar to opioid drugs (e.g., morphine) but without the associated side effects and risks.26,69 Hence, ketorolac tromethamine provides a reasonable alternative for nonopioid management of postoperative pain and may be especially valuable when opioid side effects (sedation, respiratory depression) are harmful or undesirable.12,26

cers), but beneficial effects in these other cancers requires additional study.3,74 It appears that certain prostaglandins help promote tumor growth and that aspirin and similar NSAIDs exert anticancer effects by inhibiting the synthesis of these prostaglandins.17,78 Hence, aspirin continues to gain acceptance as an anticancer drug, especially in individuals who are at an increased risk for developing colon cancer.

Problems and Adverse Effects of Aspirinlike Drugs

Gastrointestinal Problems
The primary problem with all NSAIDs, including aspirin, is gastrointestinal damage. Problems ranging from minor stomach discomfort to variable amounts of upper gastrointestinal hemorrhage and ulceration are fairly common.38,67 These effects are most likely caused by the loss of protective prostaglandins from the mucosal lining. Certain prostaglandins such as PGI2 and PGE2 are produced locally in the stomach, and these prostaglandins help protect the gastric mucosa by inhibiting gastric acid secretion, increasing the production of mucous in the stomach lining, and maintaining blood flow to the gastric mucosa.84 By inhibiting the formation of these protective prostaglandins, aspirin and most traditional NSAIDs render the stomach more susceptible to damage from acidic gastric juices.79 Certain patients are likewise more susceptible to gastrointestinal injury from aspirinlike drugs. Factors such as advanced age, a history of ulcers, use of multiple NSAIDs, use of high doses of an NSAID, and use of other agents (anti-inflammatory steroids, anticoagulants) appear to increase the risk of serious gastrointestinal damage.81 Helicobacter pylori, a bacterium that is sometimes present in the stomach (see Chapter 27), can also contribute to the increased risk of gastric irritation associated with NSAIDs.4,23 Several pharmacologic and nonpharmacologic strategies have been employed to manage gastrointestinal problems associated with aspirinlike drugs. One strategy has been to coat the aspirin tablet so that dissolution and release of the drug is delayed until it reaches the small intestine. These so-called entericcoated forms of aspirin spare the stomach from irritation, but the duodenum and upper small intestine may still be subjected to damage.38 Enteric-coated aspirin also has the disadvantage of delaying the onset of analgesic effects to relieve acute pain. Other methods such as buffering the aspirin tablet have also been used

Treatment of Fever
Although the use of aspirin in treating fever in children is contraindicated (because of the association with Reye syndrome; see Problems and Adverse Effects of Aspirinlike Drugs), aspirin remains the primary NSAID used in treating fever in adults.9 Ibuprofen is also used frequently as a nonprescription antipyretic NSAID in both adults and children.

Treatment of Vascular Disorders

As discussed previously, aspirin inhibits plateletinduced thrombus formation through its ability to inhibit thromboxane biosynthesis. Aspirin has therefore been used to help prevent the onset or recurrence of heart attacks in some individuals by inhibiting thrombus formation in the coronary arteries.97,109 Similarly, daily aspirin use may help prevent transient ischemic attacks and stroke by preventing cerebral infarction in certain patients.97,109 The role of aspirin in treating coagulation disorders is discussed in more detail in Chapter 25

Prevention of Cancer
There is now considerable evidence that regular aspirin use decreases the risk of colorectal cancer.1,49,58 It has been estimated, for example, that people who use aspirin on a regular basis have a 40 to 50 percent lower risk of fatal colon cancer as compared with people who do not use aspirin.78 Aspirin might also help prevent other types of cancers (e.g., skin, bladder, prostate can-

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to help decrease stomach irritation. The rationale is that including a chemical buffer helps blunt the acidic effects of the aspirin molecule on the stomach mucosa. It is questionable, however, whether sufficient buffer is added to commercial aspirin preparations to actually make a difference in stomach irritation. During chronic aspirin therapy (e.g., treatment of arthritis), taking aspirin with meals may help decrease gastrointestinal irritation because the food in the stomach will offer some direct protection of the gastric mucosa. The presence of food, however, will also delay drug absorption, which may decrease the peak levels of drug that reach the bloodstream. Recently, a great deal of attention has focused on other drugs that can prevent or treat the gastrointestinal side effects associated with aspirin and the other NSAIDs. Misoprostol (Cytotec) is a prostaglandin E1 analog that inhibits gastric acid secretion and prevents gastric damage.23,43 This drug has been beneficial in decreasing aspirin-induced irritation, but the clinical use of misoprostol is limited by side effects such as diarrhea.43 Omeprazole (Prilosec), esomeprazole (Nexium), and lansoprazole (Prevacid) are drugs that inhibit the proton pump that is ultimately responsible for secreting gastric acid from mucosal cells into the lumen of the stomach (see Chapter 27). These proton pump inhibitors have therefore been used successfully to increase healing and decrease NSAID-induced ulcers.34,43 Drugs that antagonize certain histamine receptorsthat is, the H2 receptor blockershave also been used to decrease gastrointestinal damage.43 As indicated in Chapter 27, histamine receptor (H2) blockers such as cimetidine (Tagamet) and ranitidine (Zantac) inhibit gastric acid secretion by antagonizing histamine receptors in the gastric mucosa. These drugs are tolerated quite well but are generally not as effective in controlling NSAID-induced ulceration as other drugs such as misoprostol and proton pump inhibitors.54 Hence, currently available drugs such as misoprostol, proton pump inhibitors, and H2 receptor blockers can be used to prevent or treat gastrointestinal damage in patients taking aspirin and other NSAIDs. These protective agents are not usually prescribed to every person taking aspirinlike drugs but are typically reserved for people who exhibit symptoms of gastrointestinal irritation or who are at risk for developing ulceration while undergoing NSAID therapy.64 COX-2 selective drugs comprise an alternative strategy for reducing the risk of gastric irritation. As indicated earlier, the COX-1 enzyme is responsible for synthesizing prostaglandins that help protect the

stomach lining, whereas the COX-2 form synthesizes prostaglandins that promote pain, inflammation, and other pathological symptoms. A COX-2 drug is therefore more likely to inhibit production of the pathological prostaglandins, while sparing the production of beneficial prostaglandins in the stomach.34,43 Indeed, COX-2 drugs are generally associated with a reduced incidence of gastric irritation.4,25,54,57 Still, certain people can experience gastric problems with COX-2 drugs, and these drugs may produce other serious side effects. The risks and benefits of COX-2 drugs are addressed in more detail later in this chapter.

Other Side Effects

Aspirin and similar NSAIDs can cause other toxic side effects if used improperly or if taken by patients who have preexisting diseases. For instance, serious hepatotoxicity is rare with normal therapeutic use, but high doses of aspirinlike drugs can produce adverse changes in hepatic function in patients with liver disease.85,99 Likewise, aspirin does not seem to cause renal disease in an individual with normal kidneys,84 but problems such as nephrotic syndrome, acute interstitial nephritis, and even acute renal failure have been observed when aspirin is given to patients with impaired renal function, or people with decreased body water (volume depletion).35,102 Aspirinlike drugs appear to cause renal and hepatic problems by inhibiting the synthesis of prostaglandins that serve a protective role in maintaining blood flow and function in the liver and kidneys.36,84 These protective prostaglandins appear to be important in sustaining adequate hepatic and renal function, especially when blood flow and perfusion pressure to these organs becomes compromised. Consequently, aspirin and aspirinlike drugs may create problems in other conditions such as hypovolemia, shock, hepatic cirrhosis, congestive heart failure, and hypertension.36,84,102 In cases of aspirin overdose, a condition known as aspirin intoxication or poisoning may occur. This event is usually identified by a number of symptoms, including headache, tinnitus, difficulty hearing, confusion, and gastrointestinal distress. More severe cases also result in metabolic acidosis and dehydration, which can be life-threatening. In adults, a dose of 10 to 30 g of aspirin is sometimes fatal, although much higher doses (130 g in one documented case) have been ingested without causing death.84 Of course, much smaller doses can produce fatalities in children.


SECTION 4 Drugs Used to Treat Pain and Inflammation

Evidence has suggested that aspirin may also be associated with a relatively rare condition known as Reye syndrome.22 This condition occurs in children and teenagers, usually following a bout of influenza or chicken pox. Reye syndrome is marked by a high fever, vomiting, liver dysfunction, and increasing unresponsiveness, often progressing rapidly and leading to delirium, convulsions, coma, and possibly death. Because aspirin is one factor that may contribute to Reye syndrome, it is recommended that aspirin and other aspirinlike drugs not be used to treat fever in children and teenagers.84 Nonaspirin antipyretics such as acetaminophen and ibuprofen are not associated with Reye syndrome, so products containing these drugs are preferred for treating fever in children and teenagers.84 A small number of individuals exhibit aspirin intolerance or supersensitivity.84 These individuals comprise approximately 1 percent of the general population, but the incidence is considerably higher (10%25%) in people with asthma or other hypersensitivity reactions.84,94 People with aspirin intolerance will display allergiclike reactions, including acute bronchospasm, urticaria, and severe rhinitis, within a few hours after taking aspirin and aspirinlike NSAIDs.45,76 These reactions may be quite severe, and cardiovascular shock may occur. Likewise, sensitivity to aspirin often indicates a concomitant sensitivity to other NSAIDs, including COX-2 selective drugs.92 Consequently, the use of all NSAIDs is contraindicated in these individuals.84 Finally, there is preliminary evidence that aspirin and other commonly used NSAIDs may inhibit healing of certain tissues. In particular, it has been suggested that these drugs may inhibit bone healing after fracture and certain types of surgery (spinal fusion).47,98 It seems that certain prostaglandins are important in stimulating the early stages of bone formation following fracture or bone surgery.42 By inhibiting the synthesis of these prostaglandins, NSAIDS may retard bone healing and delay the formation of new bone.47 Much of this evidence, however, is based on laboratory studies on animal models, and a definitive link between NSAIDs (including COX-2 drugs) and delayed bone healing in humans remains to be determined.18,106 Still, some experts feel that it might be prudent to avoid the use of NSAIDs immediately following fracture or bone surgery.31,98 More details are needed to determine if traditional NSAIDs and COX-2 selective agents are detrimental to bone heal-

ing in clinical situations, and whether these drugs should be avoided for a certain period following fracture or spinal surgery. The effect of NSAIDs on healing of soft tissues is likewise uncertain. It was originally suggested that NSAIDs might inhibit the synthesis and transport of connective tissue components such as proteoglycans.29,51 More recent findings indicate that NSAIDs may actually facilitate the incorporation of proteoglycans, hylauronan, and other components into soft tissues.8 As such, NSAIDs may enhance the healing of soft tissues in certain conditions.31 Once again, much of this evidence was obtained from animal and in vitro studies, and additional research will therefore be needed to determine if aspirin and other NSAIDs can affect the healing process of articular cartilage and other soft tissues.

Comparison of Aspirin with Other NSAIDs

A number of drugs that bear a functional similarity to aspirin have been developed during the past several decades, and a comprehensive list of currently available NSAIDs is shown in Table 152. Other NSAIDs are like aspirin in that they exert their therapeutic effects by inhibiting prostaglandin and thromboxane synthesis. Although specifically approved uses of individual members of this group vary, NSAIDs are used in much the same way as aspirin; that is, they are administered primarily for their analgesic and antiinflammatory effects, with some members also used as antipyretic and anticoagulant agents. Dosages commonly used to achieve analgesic or anti-inflammatory effects with some of the more common NSAIDs are listed in Table 153. With respect to therapeutic effects, there is no clear evidence that any of the commonly used NSAIDs are markedly better than aspirin as anti-inflammatory analgesics.87 The primary differences between aspirin and other NSAIDs are related to the side effects and safety profile of each agent (see Table 152).84 As a group, the nonaspirin NSAIDs tend to be associated with less gastrointestinal discomfort than plain aspirin, but most of these NSAIDs (with the possible exception of the COX-2 drugs; see later) are still associated with some degree of stomach irritation (Table 152).72,87 Likewise, certain NSAIDs may offer an advantage over aspirin or other aspirinlike drugs because they are

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Table 152
Generic Name Aspirin


Trade Name(s) Many trade names Specific CommentsComparison to Other NSAIDs Most widely used NSAID for analgesic and anti-inflammatory effects; also used frequently for antipyretic and anticoagulant effects. Substantially more potent than naproxen and several other NSAIDs; adverse side effects occur in 20% of patients. Has potency 34 times greater than aspirin in terms of analgesic and anti-inflammatory effects but lacks antipyretic activity. Effective as analgesic/anti-inflammatory agent with fewer side effects than most NSAIDs; may have gastric-sparing properties. GI side effects fairly common but usually less intense than those occurring with similar doses of aspirin. Similar to aspirins benefits and side effects; also available as topical ophthalmic preparation (Ocufen). First nonaspirin NSAID also available in nonprescription form; fewer GI side effects than aspirin but GI effects still occur in 5%15% of patients. Relative high incidence of dose-related side effects; problems occur in 25%50% of patients. Similar to aspirins benefits and side effects but has relatively short half-life (12 hours). Can be administered orally or by intramuscular injection; parenteral doses provide postoperative analgesia equivalent to opioids. No apparent advantages or disadvantages compared to aspirin and other NSAIDs. No advantages; often less effective and more toxic than aspirin and other NSAIDs. Effective as analgesic/anti-inflammatory agent with fewer side effects than most NSAIDs. Similar to ibuprofen in terms of benefits and adverse effects Analgesic and anti-inflammatory effects similar to aspirin; may produce fewer side effects than other NSAIDs. Potent anti-inflammatory effects but long-term use limited by high incidence of side effects (10%45% of patients). Long half-life (45 hours) allows once-daily dosing; may be somewhat better tolerated than aspirin.
(Continued on following page)












Motrin, many others




Orudis, Oruvail, others





Mefanamic acid




Naproxen Oxaprozin

Anaprox, Naprosyn, others Daypro






SECTION 4 Drugs Used to Treat Pain and Inflammation

Table 152
Generic Name Sulindac


Trade Name(s) Clinoril Specific CommentsComparison to Other NSAIDs Relatively little effect on kidneys (renal-sparing), but may produce more GI side effects than aspirin. Similar to aspirins benefits and side effects but must be given frequently (QID) because of short half-life (1 hour).




nonsteroidal anti-inflammatory drugs, GI

Table 153


Dosages (According to Desired Effect)

Drug Aspirin (many trade names) Diclofenac (Voltaren)

Analgesia 325650 mg every 4 hr Up to 100 mg for the first dose; then up to 50 mg TID thereafter

Anti-inflammation 3.65.4 g/d in divided doses Initially: 150200 mg/d in 34 divided doses; try to reduce to 75100 mg/d in 3 divided doses 250500 mg BID

Diflunisal (Dolobid)

1 g initially; 500 mg every 812 hr as needed 400 mg initially; 200400 mg every 68 hours as needed

Etodolac (Lodine)

400 mg BID or TID or 300 mg TID or QID; total daily dose is typically between 6001200 mg/d 300600 mg TID or QID 200300 mg/d in 24 divided doses 1.23.2 g/d in 34 divided doses

Fenoprofen (Nalfon) Flurbiprofen (Ansaid) Ibuprofen (Advil, Motrin, Nuprin, others) Indomethacin (Indocin)

200 mg every 46 hr 200400 mg every 46 hr as needed

2550 mg 24 times each day initially; can be increased up to 200 mg/d as tolerated 150300 mg/d in 34 divided doses 200400 mg/d in 34 divided doses

Ketoprofen (Orudis) Meclofenamate (Meclomen) Mefenamic acid (Ponstel)

2550 mg every 68 hr 50 mg every 46 hr

500 mg initially; 250 mg every 6 hr as needed

Nabumetone (Relafen)

Initially: 1000 mg/d in a single dose or 2 divided doses. Can be increased to 15002000 mg/d in 2 divided doses if needed

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Drug Naproxen (Naprosyn)

Analgesia 500 mg initially; 250 mg every 68 hr 500650 mg initially; 275 mg every 68 hr

Anti-inflammation 250, 375, or 500 mg BID

Naproxen sodium (Aleve, Anaprox, others) Oxaprozin (Daypro)

275 or 550 mg BID

Initially: 1200 mg/d, then adjust to patient tolerance 300600 mg/d in 34 divided doses initially; reduce as tolerated to lowest effective dose 20 mg/d single dose; or 10 mg BID 150 or 200 mg BID 400 mg TID initially; 600 mg1.8 g/day in 34 divided doses

Phenylbutazone (Butazolidin, Cotylbutazone) Piroxicam (Feldene) Sulindac (Clinoril) Tolmetin (Tolectin)

less toxic to other organs such as the liver and kidneys. The effect on these other organs, however, seems to be related more to the status of each patient rather than the drug. That is, all NSAIDs, including aspirin, are relatively safe in people with normal liver and kidney function when administered at moderate dosages for a short period of time.84 A specific patient may also respond more favorably to a specific NSAID in terms of therapeutic effects (decreased pain, inflammation), but these responses are due to patient variability rather than a unique characteristic of the drug. Hence, it cannot be generalized that the non-aspirin NSAIDs are significantly better or worse than aspirin in terms of either therapeutic or adverse effects.84 The primary difference between aspirin and other NSAIDs is cost. Most of the NSAIDs still require a physicians prescription. The cost of prescription NSAIDs can be anywhere from 10 to 20 times more expensive than an equivalent supply of aspirin. NSAIDs that are available in nonprescription form (e.g., ibuprofen) can still cost up to five times as much as aspirin. Consequently, the newer NSAIDs have not always been shown to be clinically superior to aspirin, but some agents may provide better effects in some patients. Considering the interpatient variability in drug response, there are surely cases in which another NSAID will produce better therapeutic effects with

fewer side effects than aspirin.108 If a patient responds equally well to a variety of NSAIDs, however, efforts should be made to use the NSAID that will produce adequate therapeutic effects at a minimal cost.84

COX-2 Selective Drugs

As discussed earlier, the cyclooxygenase enzyme that synthesizes prostaglandins exists in at least two forms: COX-1 and COX-2.24,37,103 Aspirin and most other NSAIDs are nonselective cyclooxygenase inhibitors; that is, they inhibit both the COX-1 and COX-2 forms of the cyclooxygenase. This nonselective inhibition results in decreased synthesis of prostaglandins that cause pain and inflammation (COX-2 prostaglandins), as well as loss of prostaglandins that are protective and beneficial to tissues such as the stomach lining and kidneys (COX-1 prostaglandins). Recently, drugs have been developed that are selective for the COX-2 enzyme, hence the name COX-2 inhibitors. COX-2 selective drugs such as celecoxib (Celebrex) offer the obvious advantage of inhibiting synthesis of the inflammatory prostaglandins, while sparing synthesis of beneficial prostaglandins that help regulate normal physiologic function.37,103 It follows that use of COX-2 selective drugs should decrease pain and inflammation with minimal


SECTION 4 Drugs Used to Treat Pain and Inflammation

or no adverse effects on the stomach and other tissues. The burden of evidence indicates that this fact is indeed true; that is, COX-2 drugs have analgesic and anti-inflammatory effects similar to other NSAIDs, but have a much lower incidence of gastric irritation.33,41 Likewise, COX-2 drugs do not inhibit platelet function because prostaglandins influencing normal platelet activity are under the control of the COX-1 isozyme.73 Use of COX-2 drugs should therefore be beneficial in people who are at risk for prolonged bleeding and hemorrhage. COX-2 drugs represent an important addition to the NSAID armamentarium. Although these drugs are not necessarily more effective in reducing pain and inflammation, they may avoid the gastritis associated with aspirin and other NSAIDs. The COX-2 drugs are not devoid of side effects, of course, and they may increase the risk of upper respiratory tract infections. Even though these drugs are purportedly easier on the stomach than traditional NSAIDs, certain patients may still experience gastrointestinal (GI) problems such as diarrhea, heartburn, stomach cramps, and upper GI bleeding. Nonetheless, COX-2 drugs offer an alternative to more traditional NSAIDs, and COX-2 agents may be especially useful to patients who cannot tolerate aspirin or other NSAIDs because of gastric irritation or other side effects with aspirin and the more traditional NSAIDs typically associated.33

drugs. This finding was the primary reason that certain COX-2 drugs such as rofecoxib (Vioxx) and valdecoxib (Bextra) were taken off the market. On the other hand, there is growing evidence that the risk of heart attack and stroke may be acceptable if COX-2 drugs are used appropriately.90,105,107 That is, patients must be screened carefully to determine individuals who are at risk for coronary or carotid ischemia.28,60 Dosages must likewise be kept to a minimum to prevent untoward cardiovascular events. At the time of this writing, celecoxib (Celebrex) is the only COX-2 selective drug that is still available. It will be interesting to see if new COX-2 drugs can be developed that have an acceptable cardiovascular risk profile. Likewise, efforts continue to clearly identify patients who should not take these drugs because of an increased risk for heart attack or ischemic stroke.

Acetaminophen (known also as paracetamol) has several distinct differences from aspirin and the other NSAIDs. Acetaminophen does appear to be equal to aspirin and NSAIDs in terms of analgesic and antipyretic effects, but it does not have any appreciable anti-inflammatory or anticoagulant effects.44,84 One major advantage of acetaminophen is that this drug is not associated with upper gastrointestinal tract irritation.82 Consequently, acetaminophen has been used widely in the treatment of noninflammatory conditions associated with mild-to-moderate pain and in patients who have a history of gastric damage (such as ulcers). Acetaminophen is, for example, often the first drug used to control pain in the early stages of osteoarthritis and other musculoskeletal conditions that do not have an inflammatory component.5,104,111 In addition, Reye syndrome has not been implicated with acetaminophen use, so this drug is often used in treating fever in children and teenagers.82 The mechanism of action of acetaminophen is not fully understood. Acetaminophen does inhibit the cyclooxygenase enzyme, and its analgesic and antipyretic effects are probably mediated through prostaglandin inhibition. Why acetaminophen fails to exert anti-inflammatory and anticoagulant effects, however, is unclear. One explanation is that acetaminophen preferentially inhibits central nervous system (CNS) prostaglandin production but has little effect on peripheral cyclooxygenase activity.10,44 This specific effect on central prostaglandins has generated the theory that a third subset of cyclooxygenase enzymes known

COX-2 Drugs and the Risk of Heart Attack and Stroke

The primary concern about COX-2 drugs is that certain patients taking specific agents may have an increased risk of serious cardiovascular events such as heart attack and stroke.14,75 By inhibiting the COX-2 form of the enzyme, these drugs inadvertently impair the production of prostacyclin, a prostaglandin that promotes vasodilation and prevents platelet-induced occlusion in the coronary and carotid arteries.32,63 Simultaneously, these drugs do not inhibit the production of thromboxane from the COX-1 enzyme, and thromboxane is a prostaglandin that facilitates platelet aggregation and clot formation.39 The balance of prostaglandin production is therefore shifted to favor increased platelet activity and an increased risk of clots in the coronary and carotid arteries in susceptible individuals.6 Thus, people who are prone to coronary ischemia or carotid occlusion may be at risk for heart attack or ischemic stroke when taking these COX-2 selective

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as the COX-3 variant exists in the CNS, and that acetaminophen may be somewhat selective for this COX3 subtype.11 The existence and functional role of such a COX-3 enzyme, however, remains to be fully determined. Nonetheless, acetaminophens analgesic and antipyretic effects are produced by specifically limiting prostaglandin production in central pain interpretation and thermoregulatory centers, respectively. Tissue inflammation and platelet aggregation would be peripheral events unaffected by acetaminophen, according to this theory. Hence, acetaminophen is a very important and useful medication in the treatment of fever and mild to moderate pain. The fact that acetaminophen does not cause gastric irritation might also give users the false impression that it is a totally innocuous drug devoid of all adverse effects. On the contrary, high doses of acetaminophen (e.g., 15 g) can be especially toxic to the liver and may be fatal because of hepatic necrosis.59,65,82 Normally, acetaminophen is metabolized in the liver via a series of reactions illustrated in Figure 153. In the liver, acetaminophen is converted initially into a highly reactive intermediate by-product known as N-acetyl-p-benzoquinoneimine (NAPQI). This intermediate by-product is quickly detoxified by coupling it with glutathione (GHS) to create a final, nonreactive by-product (mercapturic acid) that is sent to the kidneys for excretion. At moderate doses, these reactions occur rapidly so that NAPQI does not accumulate within the liver. At high doses, however, the conversion of NAPQI to mercapturic acid is delayed, resulting in the accumulation of NAPQI. In sufficient amounts, this metabolite induces hepatic necrosis by binding to and inactivating certain liver proteins.52 Likewise, previous damage to the liver may impair the ability of this organ to convert NAPQI to mercapturic acid, thus resulting in accumulation and damage even at relatively low doses. Hence, people with pre-existing liver disease or individuals who are chronic alcohol abusers may be particularly susceptible to liver damage caused by high doses of acetaminophen.84,86


Liver Cell

Acetaminophen N-hydroxylation


Mercapturic acid

Excreted in Urine
FIGURE 153 Acetaminophen metabolism. In the liver, acetaminophen is metabolized to a toxic intermediate N-acetyl-pbenzoquinoneimine (NAPQI). NAPQI is quickly detoxified by conjugation with glutathione (GSH), forming mercapturic acid, which is eliminated via the urine. High doses of acetaminophen or liver dysfunction can result in accumulation of NAPQI and subsequent toxicity to liver proteins.

Pharmacokinetics of NSAIDs and Acetaminophen

Aspirin is absorbed readily from the stomach and small intestine. Approximately 80 to 90 percent of aspirin remains bound to plasma proteins such as albumin. The remaining 10 to 20 percent is widely distributed throughout the body. The unbound or free drug exerts

the therapeutic effects. Aspirin itself (acetylsalicylic acid) is hydrolyzed to an active metabolitesalicylic acid. This biotransformation occurs primarily in the bloodstream, and the salicylic acid is further metabolized by oxidation or conjugation in the liver. Excretion of salicylic acid and its metabolites occurs through the kidneys. Although there is some pharmacokinetic variability within the nonaspirin NSAIDs, these drugs generally follow a pattern of absorption, protein binding, metabolism, and excretion similar to that of aspirin. Acetaminophen is also absorbed rapidly and completely from the upper gastrointestinal tract. Plasma protein binding with acetaminophen is highly variable (20 to 50 percent) but is considerably less than with aspirin. As indicated earlier in this chapter, metabolism of acetaminophen occurs in the liver via conjugation with an endogenous substrate (glutathione), and the conjugated metabolites are excreted through the kidneys.


SECTION 4 Drugs Used to Treat Pain and Inflammation

Special Concerns in Rehabilitation Patients

Aspirin and the other NSAIDs are among the most frequently used drugs in the rehabilitation population. Aside from the possibility of stomach discomfort, these drugs have a remarkable lack of adverse effects that could directly interfere with physical and occupational therapy. When used for various types of musculoskeletal pain and inflammation, these drugs can often provide analgesia without sedation and psychomimetic (hallucinogenic, etc.) effects that are associated with opioid (narcotic) analgesics. Thus, the therapy session can be conducted with the benefit of pain relief but without the loss of patient attentiveness and concentration. In inflammatory conditions, NSAIDs can be used for prolonged periods without the serious side effects associated with steroidal drugs (see Chapters 16 and 29). Of course, the limitation of NSAIDs is that they may not be as effective in moderate-to-severe pain or in severe, progressive inflammation. Still, these agents are a beneficial adjunct in many painful conditions and can usually help facilitate physical rehabilitation by relieving pain. The other clinical uses of these drugs (antipyresis, anticoagulation) may also be encountered in some patients, and these effects are also usually achieved with a minimum of adverse effects. Acetaminophen is also frequently employed for pain relief in many physical rehabilitation patients. Remember that this drug is equal to an NSAID in analgesic properties, but lacks antiinflammatory effects. Because both aspirin and acetaminophen are available without prescription, a patient may inquire about the differences between these two drugs. Clinicians should be able to provide an adequate explanation of the differential effects of aspirin and acetaminophen but should also remember that the suggested use of these agents should ultimately come from a physician.

Nonsteroidal AntiInflammatory Drugs
Brief History. D.B., a 38-year-old man, began to develop pain in his right shoulder. He was employed as a carpenter and had recently been working rather long hours building a new house. The increasing pain required medical attention. A physician evaluated the patient, and a diagnosis of subacromial bursitis was made. The patient was also referred to physical therapy, and a program of heat, ultrasound, and exercise was initiated to help resolve this condition. Problem/Influence of Medication. During the initial physical therapy evaluation, the therapist asked if the patient was taking any medication for the bursitis. The patient responded that he had been advised by the physician to take aspirin as needed to help relieve the pain. When asked if he had done this, the patient said that he had taken some aspirin once or twice, especially when his shoulder pain kept him awake at night. When he was asked specifically what type of aspirin he had taken, he named a commercial acetaminophen preparation. Evidently the patient was unaware of the difference between acetaminophen and aspirin (acetylsalicylate). Decision/Solution. The therapist explained the difference between aspirin and acetaminophen to the patient, pointing out that acetaminophen lacks any significant antiinflammatory effects. After consulting with the physician to confirm that aspirin was recommended, the therapist suggested that the patient take the recommended dosage at regular intervals to help decrease the inflammation in the bursa, as well as to provide analgesia. The patient had used aspirin in the past without any problems, but the therapist cautioned the patient to contact his physician if any adverse effects were noted (e.g., gastrointestinal distress or tinnitus).

Chapter 15

Nonsteroidal Anti-Inflammatory Drugs


Aspirin and similarly acting drugs comprise a group of therapeutic agents that are usually referred to as NSAIDs. In addition to their anti-inflammatory effects, these drugs are also known for their ability to decrease mild-to-moderate pain (analgesia), alleviate fever (antipyresis), and inhibit platelet aggregation (anticoagulation). These drugs seem to exert all of their therapeutic effects by inhibiting the function of the cellular cyclooxygenase enzyme, which results in decreased prostaglandin and thromboxane synthesis. Aspirin is the prototypical NSAID, and newer prescription and nonprescription drugs appear to be similar in terms of pharmacologic effects and therapeutic efficacy. Newer drugs known as COX-2 inhibitors were also developed in an attempt to inhibit prostaglandins

that cause pain and inflammation while sparing the production of beneficial prostaglandins that protect the stomach and other organs. These COX-2 drugs have the potential to produce therapeutic effects with less gastritis, but their status remains controversial because certain COX-2 agents may increase the risk of heart attack and stroke. Acetaminophen also seems to be similar to aspirin in analgesic and antipyretic effects, but acetaminophen lacks anti-inflammatory and anticoagulant properties. Patients requiring physical rehabilitation use aspirin, other NSAIDs, and COX-2 inhibitors frequently, which usually provides beneficial effects (analgesia, decreased inflammation, etc.) without producing cognitive side effects (sedation, mood changes) that can interfere with the rehabilitation program.

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SECTION 4 Drugs Used to Treat Pain and Inflammation 42. Gerstenfeld LC, Einhorn TA. COX inhibitors and their effects on bone healing. Expert Opin Drug Saf. 2004;3:131136. 43. Goldstein JL. Challenges in managing NSAIDassociated gastrointestinal tract injury. Digestion. 2004;69(suppl 1):2533. 44. Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005;12:4655. 45. Grattan CE. Aspirin sensitivity and urticaria. Clin Exp Dermatol. 2003;28:123127. 46. Gyires K. Gastric mucosal protection: from prostaglandins to gene-therapy. Curr Med Chem. 2005;12:203215. 47. Harder AT, An YH. The mechanisms of the inhibitory effects of nonsteroidal anti-inflammatory drugs on bone healing: a concise review. J Clin Pharmacol. 2003; 43:807815. 48. Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther. 2004;103: 147166. 49. Hawk ET, Levin B. Colorectal cancer prevention. J Clin Oncol. 2005;23:378391. 50. Helliwell RJ, Adams LF, Mitchell MD. Prostaglandin synthases: recent developments and a novel hypothesis. Prostaglandins Leukot Essent Fatty Acids. 2004;70:101 113. 51. Henrotin Y, Bassleer C, Franchimont P. In vitro effects of etodolac and acetylsalicylic acid on human chondrocyte metabolism. Agents Actions. 1992;36:317323. 52. Hinson JA, Reid AB, McCullough SS, James LP. Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab Rev. 2004;36:805822. 53. Hinz B, Brune K. Pain and osteoarthritis: new drugs and mechanisms. Curr Opin Rheumatol. 2004;16: 628633. 54. Hooper L, Brown TJ, Elliott R, et al. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal antiinflammatory drugs: systematic review. BMJ. 2004; 329:948. 55. Ivanov AI, Romanovsky AA. Prostaglandin E2 as a mediator of fever: synthesis and catabolism. Front Biosci. 2004;9:19771993. 56. Jabbour HN, Sales KJ. Prostaglandin receptor signalling and function in human endometrial pathology. Trends Endocrinol Metab. 2004;15:398404. 57. Jacobsen RB, Phillips BB. Reducing clinically significant gastrointestinal toxicity associated with nonsteroidal antiinflammatory drugs. Ann Pharmacother. 2004;38:14691481. 58. Jalving M, Koornstra JJ, De Jong S, et al. Review article: the potential of combinational regimen with non-steroidal anti-inflammatory drugs in the chemoprevention of colorectal cancer. Aliment Pharmacol Ther. 2005;21:321339. 59. James LP, Mayeux PR, Hinson JA. Acetaminopheninduced hepatotoxicity. Drug Metab Dispos. 2003;31: 14991506.

23. Chan FK, Graham DY. Review article: prevention of non-steroidal anti-inflammatory drug gastrointestinal complicationsreview and recommendations based on risk assessment. Aliment Pharmacol Ther. 2004;19: 10511061. 24. Chandrasekharan NV, Simmons DL. The cyclooxygenases. Genome Biol. 2004;5:241. 25. Chang SY, Howden CW. Is no NSAID a good NSAID? Approaches to NSAID-associated upper gastrointestinal disease. Curr Gastroenterol Rep. 2004;6: 447453. 26. Chen JY, Wu GJ, Mok MS, et al. Effect of adding ketorolac to intravenous morphine patient-controlled analgesia on bowel function in colorectal surgery patientsa prospective, randomized, double-blind study. Acta Anaesthesiol Scand. 2005;49:546551. 27. Cheng HF, Harris RC. Cyclooxygenases, the kidney, and hypertension. Hypertension. 2004;43:525530. 28. Clark DW, Layton D, Shakir SA. Do some inhibitors of COX-2 increase the risk of thromboembolic events? Linking pharmacology with pharmacoepidemiology. Drug Saf. 2004;27:427456. 29. Collier S, Ghosh P. Comparison of the effects of NSAIDs on proteoglycan synthesis by articular cartilage explant and chondrocyte monolayer cultures. Biochem Pharmacol. 1991;41:13751384. 30. Creutzig A, Lehmacher W, Elze M. Meta-analysis of randomised controlled prostaglandin E1 studies in peripheral arterial occlusive disease stages III and IV. Vasa. 2004;33:137144. 31. Dahners LE, Mullis BH. Effects of nonsteroidal antiinflammatory drugs on bone formation and soft-tissue healing. J Am Acad Orthop Surg. 2004;12:139143. 32. Dai W, Kloner RA. Relationship between cyclooxygenase-2 inhibition and thrombogenesis. J Cardiovasc Pharmacol Ther. 2004;9:5159. 33. de Leval X, Julemont F, Benoit V, et al. First and second generations of COX-2 selective inhibitors. Rev Med Chem. 2004;4:597601. 34. Dickman A, Ellershaw J. NSAIDs: gastroprotection or selective COX-2 inhibitor? Palliat Med. 2004;18: 275286. 35. Ejaz P, Bhojani K, Joshi VR. NSAIDs and kidney. J Assoc Physicians India. 2004;52:632640. 36. Epstein M. Non-steroidal anti-inflammatory drugs and the continuum of renal dysfunction. J Hypertens Suppl. 2002;20:S17S23. 37. Fitzpatrick FA. Cyclooxygenase enzymes: regulation and function. Curr Pharm Des. 2004;10:577588. 38. Fortun PJ, Hawkey CJ. Nonsteroidal antiinflammatory drugs and the small intestine. Curr Opin Gastroenterol. 2005;21:169175. 39. Fowles RE. Potential cardiovascular effects of COX-2 selective nonsteroidal antiinflammatory drugs. J Pain Palliat Care Pharmacother. 2003;17:2750. 40. Francois H, Coffman TM. Prostanoids and blood pressure: which way is up? J Clin Invest. 2004;114: 757759. 41. Gajraj NM, Joshi GP. Role of cyclooxygenase-2 inhibitors in postoperative pain management. Anesthesiol Clin North America. 2005;23:4972.

Chapter 15 60. Justice E, Carruthers DM. Cardiovascular risk and COX-2 inhibition in rheumatological practice. J Hum Hypertens. 2005;19:15. 61. Kiefer W, Dannhardt G. Novel insights and therapeutical applications in the field of inhibitors of COX-2. Curr Med Chem. 2004;11:31473161. 62. Koehne CH, Dubois RN. COX-2 inhibition and colorectal cancer. Semin Oncol. 2004;31(suppl 7):1221. 63. Konstam MA, Weir MR. Current perspective on the cardiovascular effects of coxibs. Cleve Clin J Med. 2002; 69(suppl 1):SI47SI52. 64. Lanas A. Economic analysis of strategies in the prevention of non-steroidal anti-inflammatory drug-induced complications in the gastrointestinal tract. Aliment Pharmacol Ther. 2004;20:321331. 65. Lane JE, Belson MG, Brown DK, Scheetz A. Chronic acetaminophen toxicity: a case report and review of the literature. J Emerg Med. 2002;23:253256. 66. Laufer S. Role of eicosanoids in structural degradation in osteoarthritis. Curr Opin Rheumatol. 2003;15: 623627. 67. Lazzaroni M, Bianchi Porro G. Gastrointestinal sideeffects of traditional non-steroidal anti-inflammatory drugs and new formulations. Aliment Pharmacol Ther. 2004;20 (suppl 2):4858. 68. Leslie CC. Regulation of arachidonic acid availability for eicosanoid production. Biochem Cell Biol. 2004; 82:117. 69. Lowder JL, Shackelford DP, Holbert D, Beste TM. A randomized, controlled trial to compare ketorolac tromethamine versus placebo after cesarean section to reduce pain and narcotic usage. Am J Obstet Gynecol. 2003;189:15591562. 70. Marjoribanks J, Proctor ML, Farquhar C. Nonsteroidal anti-inflammatory drugs for primary dysmenorrhoea. Cochrane Database Syst Rev. 2003; CD001751. 71. Mason L, Moore RA, Edwards JE, et al. Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis. BMC Musculoskelet Disord. 2004;5:28. 72. Moore N. Forty years of ibuprofen use. Int J Clin Pract Suppl. 2003;135:2831. 73. Morrow JD, Roberts LJ. Lipid-derived autacoids: eicosanoids and platelet-activating factor. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 74. Moyad MA. An introduction to aspirin, NSAids, and COX-2 inhibitors for the primary prevention of cardiovascular events and cancer and their potential preventive role in bladder carcinogenesis: part II. Semin Urol Oncol. 2001;19:306316. 75. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954959. 76. Nettis E, Colanardi MC, Ferrannini A, Tursi A. Update on sensitivity to nonsteroidal antiinflammatory drugs. Curr Drug Targets Immune Endocr Metabol Disord. 2001;1:233240. 77. Nusing RM, Seyberth HW. The role of cyclooxygenases and prostanoid receptors in furosemide-like salt

Nonsteroidal Anti-Inflammatory Drugs


78. 79.

80. 81.

82. 83. 84.

85. 86. 87. 88. 89.


91. 92. 93. 94.


losing tubulopathy: the hyperprostaglandin E syndrome. Acta Physiol Scand. 2004;181:523528. Peek RM, Jr. Prevention of colorectal cancer through the use of COX-2 selective inhibitors. Cancer Chemother Pharmacol. 2004;54(suppl 1):S50S56. Perini R, Fiorucci S, Wallace JL. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastrointestinal injury and repair: a window of opportunity for cyclooxygenase-inhibiting nitric oxide donors. Can J Gastroenterol. 2004;18:229236. Peters-Golden M, Canetti C, Mancuso P, Coffey MJ. Leukotrienes: underappreciated mediators of innate immune responses. J Immunol. 2005;174:589594. Peura DA. Prevention of nonsteroidal antiinflammatory drug-associated gastrointestinal symptoms and ulcer complications. Am J Med. 2004;117(suppl 5A):63S71S. Prescott LF. Paracetamol: past, present, and future. Am J Ther. 2000;7:143147. Riccioni G, Di Ilio C, Conti P, et al. Advances in therapy with antileukotriene drugs. Ann Clin Lab Sci. 2004; 34:379387. Roberts LJ, Morrow JD. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. Rubenstein JH, Laine L. Systematic review: the hepatotoxicity of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2004;20:373380. Rumack BH. Acetaminophen misconceptions. Hepatology. 2004;40:1015. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician. 2005;71:913918. Sales KJ, Jabbour HN. Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium. Reproduction. 2003;126:559567. Schnitzer TJ, Ferraro A, Hunsche E, Kong SX. A comprehensive review of clinical trials on the efficacy and safety of drugs for the treatment of low back pain. J Pain Symptom Manage. 2004;28:7295. Shaya FT, Blume SW, Blanchette CM, et al. Selective cyclooxygenase-2 inhibition and cardiovascular effects: an observational study of a Medicaid population. Arch Intern Med. 2005;165:181186. Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004;56:387437. Stevenson DD. Aspirin and NSAID sensitivity. Immunol Allergy Clin North Am. 2004;24:491505. Sublette ME, Russ MJ, Smith GS. Evidence for a role of the arachidonic acid cascade in affective disorders: a review. Bipolar Disord. 2004;6:95105. Szczeklik A, Sanak M, Nizankowska-Mogilnicka E, Kielbasa B. Aspirin intolerance and the cyclooxygenaseleukotriene pathways. Curr Opin Pulm Med. 2004;10: 5156. Takeeda M, Hayashi Y, Yamato M, et al. Roles of endogenous prostaglandins and cyclooxygenase izoenzymes in mucosal defense of inflamed rat stomach. J Physiol Pharmacol. 2004;55:193205.


SECTION 4 Drugs Used to Treat Pain and Inflammation or acetaminophen for osteoarthritis of the hip or knee? A systematic review of evidence and guidelines. J Rheumatol. 2004;31:344354. Weir MR, Sperling RS, Reicin A, Gertz BJ. Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program. Am Heart J. 2003;146:591604. Wheeler P, Batt ME. Do non-steroidal antiinflammatory drugs adversely affect stress fracture healing? A short review. Br J Sports Med. 2005;39: 6569. White WB, Strand V, Roberts R, Whelton A. Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am J Ther. 2004; 11:244250. Willkens RF. The selection of a nonsteroidal antiinflammatory drug: is there a difference? J Rheumatol. 1992;19(suppl 36):912. Williams A, Hennekens CH. The role of aspirin in cardiovascular diseasesforgotten benefits? Expert Opin Pharmacother. 2004;5:109115. Zha S, Yegnasubramanian V, Nelson WG, et al. Cyclooxygenases in cancer: progress and perspective. Cancer Lett. 2004;215:120. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis. 2004;63:901907.

96. Tanaka Y, Yamaki F, Koike K, Toro L. New insights into the intracellular mechanisms by which PGI2 analogues elicit vascular relaxation: cyclic AMPindependent, Gs-protein mediated-activation of MaxiK channel. Curr Med Chem Cardiovasc Hematol Agents. 2004;2:257265. 97. Tendera M, Wojakowski W. Role of antiplatelet drugs in the prevention of cardiovascular events. Thromb Res. 2003;110:355359. 98. Thaller J, Walker M, Kline AJ, Anderson DG. The effect of nonsteroidal anti-inflammatory agents on spinal fusion. Orthopedics. 2005;28:299303. 99. Traversa G, Bianchi C, Da Cas R, et al. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. BMJ. 2003;327:1822. 100. Tuynman JB, Peppelenbosch MP, Richel DJ. COX-2 inhibition as a tool to treat and prevent colorectal cancer. Crit Rev Oncol Hematol. 2004;52:81101. 101. Ueno A, Oh-ishi S. Critical roles for bradykinin and prostanoids in acute inflammatory reactions: a search using experimental animal models. Curr Drug Targets Inflamm Allergy. 2002;1:363376. 102. Ulinski T, Guigonis V, Dunan O, Bensman A. Acute renal failure after treatment with non-steroidal antiinflammatory drugs. Eur J Pediatr. 2004;163:148150. 103. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003;110:255258. 104. Wegman A, van der Windt D, van Tulder M, Stalman W, de Vries T. Nonsteroidal antiinflammatory drugs




108. 109. 110. 111.



Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis

Rheumatoid arthritis and osteoarthritis represent the two primary pathologic conditions that affect the joints and periarticular structures. Although the causes underlying these conditions are quite different from one another, both conditions can cause severe pain and deformity in various joints in the body. Likewise, pharmacologic management plays an important role in the treatment of each disorder. Because physical therapists and other rehabilitation specialists often work with patients who have rheumatoid arthritis or osteoarthritis, an understanding of the types of drugs used to treat these diseases is important. This chapter will begin by describing the etiology of rheumatoid joint disease and the pharmacologic treatment of rheumatoid arthritis. An analogous discussion of osteoarthritis will follow. Hopefully, these descriptions will provide rehabilitation specialists with an understanding of drug therapys role in arthritis, and the impact drugs can have on patients receiving physical therapy and occupational therapy. exacerbation and remission, rheumatoid arthritis is often progressive in nature, with advanced stages leading to severe joint destruction and bone erosion. Specific criteria for the diagnosis of rheumatoid arthritis in adults are listed in Table 161. In addition to the adult form of this disease, there is also a form of arthritis that occurs in children known commonly as juvenile rheumatoid arthritis, or by the more recent term juvenile idiopathic arthritis (JIA). Juvenile arthritis differs from the adult form of this diseasethe age of onset (younger than 16 years) and other criteria help to differentiate these two types of rheumatoid joint disease.69,109 Drug treatment of adult and juvenile rheumatoid arthritis is fairly similar, however, with the exception that children may not respond as well to certain medications (e.g., hydroxychloroquine, gold compounds, penicillamine) compared to adults.79,80 Consequently, in this chapter most of the discussion of the management of rheumatoid arthritis is directed toward the adult form. Rheumatoid arthritis affects about 0.5 to 1.0 percent of the population worldwide.38,55 This disease occurs three times more often in women than in men, with women between the ages of 20 and 40 especially susceptible to the onset of rheumatoid joint disease.90,101 Rheumatoid arthritis often causes severe pain and suffering, frequently devastating the patients family and social life as well as his or her job situation.5,55 The economic impact of this disease is also staggering; medical costs and loss of productivity exceed $1 billion annually in the United States.5,55 Consequently, rheu217

Rheumatoid Arthritis
Rheumatoid arthritis is a chronic, systemic disorder that affects many different tissues in the body, but is primarily characterized by synovitis and the destruction of articular tissue.49,90,100 This disease is associated with pain, stiffness, and inflammation in the small synovial joints of the hands and feet, as well as in larger joints such as the knee. Although marked by periods of


SECTION 4 Drugs Used to Treat Pain and Inflammation

Table 161


Definition Morning stiffness in and around the joints, lasting at least 1 hr before maximal improvement. At least 3 joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints. At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint. Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry). Subcutaneous nodules over bony prominences or extensor surfaces, or in juxtaarticular regions, observed by a physician. Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in 5% of normal control subjects. Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify).

1. Morning stiffness

2. Arthritis of 3 or more joint areas

3. Arthritis of hand joints 4. Symmetric arthritis

5. Rheumatoid nodules

6. Serum rheumatoid factor

7. Radiographic changes

For classification purposes, a patient is diagnosed with rheumatoid arthritis if he or she has satisfied at least 4 of these 7 criteria. Criteria 1 through 4 must have been present for at least 6 weeks. PIP proximal interphalangeal; MCP metacarpophalangeal; MTP metatarsophalangeal. Source: Arnett, et al. The American Rheumatism Association 1987 Revised Criteria for the Classification of Rheumatoid Arthritis. Arthritis and Rheumatism.1988;31:315324. Reprinted from Arthritis and Rheumatism Journal, copyright 1988. Used with permission from the American College of Rheumatology.

matoid arthritis is a formidable and serious problem in contemporary health care.

Immune Basis for Rheumatoid Arthritis

The initiating factor in rheumatoid arthritis is not known. It is apparent, however, that the underlying basis of this disease consists of some type of autoimmune response in genetically susceptible individuals.29,32,94 Some precipitating factor (possibly a virus or other infectious agent) appears to initiate the formation of antibodies that are later recognized by the host as antigens.29 Subsequent formation of new antibodies to these antigens then initiates a complex chain of

events involving a variety of immune system components such as mononuclear phagocytes, T lymphocytes, and B lymphocytes.38,100 These cells basically interact with each other to produce a number of arthritogenic mediators, including cytokines (interleukin-1, tumor necrosis factor-alpha), eicosanoids (prostaglandins, leukotrienes), and destructive enzymes (proteases, collagenases).32,90,94 These substances act either directly or through other cellular components of the immune system to induce synovial cell proliferation and destruction of articular cartilage and bone.29,100 Thus, the joint destruction in rheumatoid arthritis is the culmination of a series of events resulting from an inherent defect in the immune response in patients with this disease.29,32

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis


Overview of Drug Therapy in Rheumatoid Arthritis

The drug treatment of rheumatoid arthritis has two goals: (1) to decrease joint inflammation and (2) to arrest the progression of this disease. Three general categories of drugs are available to accomplish these goals: (1) nonsteroidal anti-inflammatory drugs (NSAIDs), (2) glucocorticoids, and (3) a diverse group of agents known as disease-modifying antirheumatic drugs (DMARDs) (Table 162).56,90 NSAIDs and glucocorticoids are used primarily to decrease joint inflammation, but these agents do not necessarily halt the progression of rheumatoid arthritis. DMARDs attempt to slow or halt the advancement of this disease, usually by interfering with the immune response that seems to be the underlying factor in rheumatoid

arthritis.56 Each of these major drug categories, as well as specific disease-modifying drugs, is discussed in the following sections.

Nonsteroidal AntiInflammatory Drugs

Aspirin and the other NSAIDs are usually considered the first line of defense in treating rheumatoid arthritis.68,90 Although NSAIDs are not as powerful in reducing inflammation as glucocorticoids, they are associated with fewer side effects, and they offer the added advantage of analgesia. Consequently, NSAIDs such as aspirin are often the first drugs employed in treating rheumatoid arthritis; in fact, this disease can often be controlled for short periods in some patients

Table 162


I. Nonsteroidal Anti-Inflammatory Drugs Aspirin (many trade names) Celecoxib (Celebrex)* Diclofenac (Cataflam, Voltaren) Diflunisal (Dolobid) Fenoprofen (Nalfon) Flurbiprofen (Ansaid) Ibuprofen (many trade names) Indomethacin (Indocin) II. Corticosteroids Betamethasone (Celestone) Cortisone (Cortone acetate) Dexamethasone (Decadron, others) Hydrocortisone (Cortef, others) III. Disease-Modifying Antirheumatic Drugs Adalimumab (Humira) Anakinra (Kineret) Auranofin (Ridaura) Aurothioglucose (Solganal) Azathioprine (Imuran) Chloroquine (Aralen) Cyclophosphamide (Cytoxan) Cyclosporine (Neoral, Sandimmune)

Ketoprofen (Orudis, others) Meclofenamate (Meclomen) Nabumetone (Relafen) Naproxen (Anaprox, Naprosyn) Oxaprozin (Daypro) Piroxicam (Feldene) Sulindac (Clinoril) Tolmetin (Tolectin)

Methylprednisolone (Medrol, others) Prednisolone (Prelone, others) Prednisone (Deltasone, others) Triamcinolone (Aristocort, others)

Etanercept (Enbrel) Gold sodium thiomalate (Myochrysine) Hydroxychloroquine (Plaquenil) Infliximab (Remicade) Leflunomide (Arava) Methotrexate (Rheumatrex, others) Penicillamine (Cuprimine, Depen) Sulfasalazine (Azulfidine)

as a cyclooxygenase type 2 (COX-2) inhibitor; see Chapter 15


SECTION 4 Drugs Used to Treat Pain and Inflammation

by solely using an NSAID.68 In patients who continue to experience progressive joint destruction despite NSAID therapy these drugs are often combined with disease-modifying agents (discussed later in this chapter). Usually, it is not advisable to use two different NSAIDs simultaneously because there is an increased risk of side effects without any appreciable increase in therapeutic benefits. Some amount of trial and error may be involved in selecting the best NSAID, and several agents may have to be given before an optimal drug is found. As discussed in Chapter 15, aspirin appears approximately equal to the newer, more expensive NSAIDs in terms of anti-inflammatory and analgesic effects, but some of the newer drugs may produce less gastrointestinal discomfort. In particular, the cyclooxygenase-2 (COX-2) selective drugs (see below) may be especially helpful in people with a history of peptic ulcers or other risk factors for gastrointestinal problems.3 The choice of a specific NSAID ultimately depends on each patients response to the therapeutic effects and side effects of any given agent.84 Finally, acetaminophen (paracetamol) products may provide some temporary analgesic effects in people with rheumatoid arthritis, but these products are not optimal because they lack anti-inflammatory effects. As discussed in Chapter 15, acetaminophen can be used to treat mild-to-moderate pain, but the lack of anti-inflammatory effects makes acetaminophen fall short of NSAIDs for conditions such as rheumatoid arthritis. Hence, patients with rheumatoid arthritis usually prefer the effects of NSAIDs to acetaminophen,110 and acetaminophen products are not typically used for the routine treatment of this disease.

these drugs inhibit the COX-1 form of the enzyme that produces beneficial and protective prostaglandins in certain tissues while also inhibiting the COX-2 form that synthesizes prostaglandins in painful and inflamed tissues.84 Newer NSAIDs, however, are known as COX-2 inhibitors because these drugs inhibit the specific form of COX-2 that synthesizes prostaglandins during pain and inflammation. COX-2 drugs such as celecoxib (Celebrex) spare the production of normal or protective prostaglandins produced by COX-1 in the stomach, kidneys, and platelets (see Chapter 15).33,103 Hence, COX-2 selective drugs may be especially beneficial during long-term use in people with rheumatoid arthritis because they may be less toxic to the stomach and other tissues.3 The effect of COX-2 selective drugs and other NSAIDs on prostaglandin biosynthesis is discussed in more detail in Chapter 15.

Adverse Side Effects

The problems and adverse effects of aspirin and other NSAIDs are discussed in Chapter 15. The most common problem with chronic use is stomach irritation, which can lead to gastric ulceration and hemorrhage. This can be resolved to some extent by taking aspirin in an enteric-coated form so that release is delayed until the drug reaches the small intestine. Other pharmacologic interventions such as prostaglandin analogs (misoprostol) and proton pump inhibitors (omeprazole [Prilosec], and so forth) can also be used if gastropathy continues to be a limiting factor during NSAID use (see Chapter 15). Chronic NSAID use can also produce bleeding problems (because of platelet inhibition) and impaired renal function, especially in an older or debilitated patient. Despite the potential for various side effects, aspirin and other NSAIDs continue to be used extensively by people with rheumatoid arthritis and are often used for extended periods without serious effects. As indicated earlier, COX-2 selective drugs may reduce the risk of toxicity to the stomach, kidneys, and other tissues because these drugs spare the production of normal or protective prostaglandins in these tissues.3 These drugs may cause other problems such as diarrhea, heartburn, gastrointestinal cramps, and an increased risk of upper respiratory tract infection. As indicated in Chapter 15, COX-2 drugs have also been associated with serious cardiovascular problems (heart attack, stroke), and these drugs should be avoided in people at risk for cardiac disease.

Mechanism of Action
The pharmacology of the NSAIDs was discussed in Chapter 15. Basically, aspirin and the other NSAIDs exert most or all of their anti-inflammatory and analgesic effects by inhibiting the synthesis of prostaglandins.84,103 Certain prostaglandins (i.e., prostaglandin E2 [PGE2]) are believed to participate in the inflammatory response by increasing local blood flow and vascular permeability and by exerting a chemotactic effect on leukocytes.61 Prostaglandins are also believed to sensitize pain receptors to the nociceptive effects of other pain mediators such as bradykinin.84 Aspirin and other NSAIDs prevent the production of prostaglandins by inhibiting the COX enzyme that initiates prostaglandin synthesis. As discussed in Chapter 15, aspirin and most other NSAIDs inhibit all COX forms; that is,

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis


Glucocorticoids such as prednisone are extremely effective anti-inflammatory agents, but they are associated with a number of serious side effects (see Adverse Side Effects, below). Hence, these drugs (known also as corticosteroids) are commonly used to treat acute exacerbations in people with rheumatoid arthritis. In particular, the judicious short-term use of systemic (oral) glucocorticoids can serve as a bridge between an acute flare-up of rheumatoid joint disease and successful management by other drugs such as NSAIDs and disease-modifying agents.43 Glucocorticoids can often be given systemically at high doses for short periods (a week or two) to provide anti-inflammatory effects. This so-called pulse treatment may be especially helpful in managing acute exacerbations of rheumatoid arthritis without producing the severe side effects associated with long-term use.50 Glucocorticoids can also be injected directly into the arthritic joint, a technique that can be invaluable in the management of acute exacerbations. There is, of course, considerable controversy about whether intra-articular glucocorticoids will produce harmful catabolic effects in joints that are already weakened by arthritic changes. At the very least, the number of injections into an arthritic joint should be limited, and a common rule of thumb is to not exceed more than four injections in one joint within one year.77 The long-term use of glucocorticoids, however, remains somewhat controversial.52,96 While their short-term anti-inflammatory effects can be extremely helpful, high doses of glucocorticoids for prolonged periods can cause serious musculoskeletal problems and other adverse effects (see below). It was also believed that these drugs do not necessarily halt the progression of rheumatoid arthritis and that their short-term benefits are eventually lost during prolonged use.102 More recent evidence, however, suggests that glucocorticoids such as prednisone may actually have some ability to retard disease progression.11,24 That is, these drugs may have some beneficial disease-modifying properties similar to other DMARDs.86 Furthermore, these beneficial effects may be achieved with fairly low doses, minimizing the risk of adverse effects.11,24 Hence, the risks and benefits of long-term glucocorticoid administration continue to be investigated, and future research will help clarify how these drugs can be used most effectively alone or with other agents to manage rheumatoid arthritis.

Mechanism of Action
The details of the cellular effects of steroids are discussed in Chapter 29. Briefly, glucocorticoids bind to a receptor in the cytoplasm of certain cells (macrophages, leukocytes), thereby forming a glucocorticoidreceptor complex.17,89 This complex then moves to the cells nucleus where it binds to specific genes that regulate the inflammatory process. By binding to these genes, the glucocorticoid-receptor complex increases the production of several anti-inflammatory proteins while also inhibiting the production of many proinflammatory substances.87 These agents, for example, increase the production of proteins called annexins (previously known as lipocortins).66 Annexins inhibit the phospholipase A2 enzyme that normally liberates fatty acid precursors at the start of prostaglandin and leukotriene biosynthesis. Therefore, glucocorticoid-induced production of annexins blocks the first step in the synthesis of proinflammatory prostaglandins and leukotrienes.66 Glucocorticoids likewise increase the production of proteins such as interleukin-10, interleukin-1 receptor antagonist, and neutral endopeptidase.8 These other proteins contribute to anti-inflammatory effects by inhibiting, destroying, or blocking various other inflammatory chemicals, peptides, and proteins.8 In addition to direct effects on genes regulating inflammation, glucocorticoids also inhibit the transcription factors that initiate synthesis of proinflammatory cytokines (e.g., interleukin-1, tumor necrosis factor), enzymes (e.g., COX-2, nitric oxide synthase), and receptor proteins (e.g., natural killer receptors).17,87,89 Glucocorticoids may also exert some of their effects via a membrane-bound receptor that regulates activity of macrophages, eosinophils, T lymphocytes, and several other types of cells involved in the inflammatory response.89 Consequently, glucocorticoids affect many aspects of inflammation, and their powerful anti-inflammatory effects in rheumatoid arthritis result from their ability to blunt various cellular and chemical components of the inflammatory response.

Adverse Side Effects

The side effects of glucocorticoids are numerous (see Chapter 29). These drugs exert a general catabolic effect on all types of supportive tissue (i.e., muscle, tendon, bone). Osteoporosis is a particular a problem in the patient with arthritis because many of these


SECTION 4 Drugs Used to Treat Pain and Inflammation

patients have significant bone loss before even beginning steroid therapy. Glucocorticoids have been known to increase bone loss in patients with arthritis, especially when these drugs are used at higher doses for prolonged periods.68,86 Glucocorticoids may also cause muscle wasting and weakness, as well as hypertension, aggravation of diabetes mellitus, glaucoma, and cataracts.68,89 These side effects emphasize the need to limit glucocorticoid therapy as much as possible in patients with arthritis.

be underlying rheumatoid disease. For example, these drugs can inhibit the function of monocytes and T and B lymphocytes, or affect specific inflammatory mediators (e.g., cytokines) that are responsible for perpetuating joint inflammation and destruction.90 The pharmacology of specific DMARDs is discussed below.

Antimalarial Drugs
Originally used in the treatment of malaria, the drugs chloroquine (Aralen) and hydroxychloroquine (Plaquenil) have also been used to treat rheumatoid arthritis. In the past, these drugs have been used reluctantly because of the fear of retinal toxicity (see Adverse Side Effects).25 There is now evidence, however, that these agents can be used safely, but they are only marginally effective when compared to other DMARDs. These drugs are therefore not usually the first choice, but they can be used in patients who cannot tolerate other DMARDs, or in combination with another DMARD (e.g., methotrexate) for more comprehensive treatment. Mechanism of Action. Antimalarials exert a number of effects, although it is unclear exactly which of these contributes to their ability to halt the progression in rheumatoid arthritis. These drugs are known to increase pH within certain intracellular vacuoles in macrophages and other immune-system cells.35 This effect is believed to disrupt the ability of these cells to process antigenic proteins and present these antigens to T cells.107 Decreased T-cell stimulation results in immunosuppression and attenuation of the arthritic response.35 Antimalarials have also been shown to stabilize lysosomal membranes and impair DNA and RNA synthesis, although the significance of these effects in their role as antiarthritics remains unclear.107 Adverse Side Effects. Chloroquine and hydroxychloroquine are usually considered the safest DMARDs.68 The major concern is that high doses of these drugs can produce irreversible retinal damage. Retinal toxicity is rare, however, when daily dosages are maintained below the levels typically used to treat rheumatoid arthritis (i.e., less than 3.5 to 4.0 mg/kg per day for chloroquine and less than 6.0 to 6.5 mg/kg per day for hydroxychloroquine).60,63 Nonetheless, ocular exams should be scheduled periodically to ensure the safe and effective use of these drugs during prolonged administration.16 Other side effects such as headache and gastrointestinal distress can occur, but these are relatively infrequent and usually transient.

Disease-Modifying Antirheumatic Drugs

Disease-modifying antirheumatic drugs (DMARDs) are defined as medications that retard or halt the progression of [rheumatoid] disease.68 These drugs comprise an eclectic group of agents that are now recognized as essential in the early treatment of rheumatoid arthritis. That is, early and aggressive use of DMARDs can slow the progression of this disease before there is extensive damage to affected joints. When used in conjunction with NSAIDs and glucocorticoids, DMARDs can help improve the long-term outcomes of patients with rheumatoid arthritis, and can contribute to substantial improvements in qualityof-life.12 Hence, disease-modifying drugs are typically used to control synovitis and erosive changes during the active stages of rheumatoid joint disease.68 There is still considerable concern, however, over DMARDs safety and efficacy. Older DMARDs, such as penicillamine and oral gold, were especially problematic, and many patients who started treatment on these drugs eventually discontinued drug therapy due to side effects or lack of therapeutic benefits.68 Some of the newer DMARDs are substantially more effective, but these newer agents can still produce serious side effects such as hepatic and renal toxicity.70 Despite these limitations, there has been a definite trend toward more frequent DMARD use, and to use these drugs earlier in the course of rheumatoid arthritis before excessive joint destruction has occurred.4,68 Disease-modifying agents currently used in treating rheumatoid arthritis are listed in Table 163. As the name implies, DMARDs attempt to induce remission by modifying the pathologic process inherent to rheumatoid arthritis. In general, DMARDs inhibit certain aspects of the immune response thought to

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis


Table 163
Drug Anakinra


Trade Name Kineret Usual Dosage Subcutaneous injection: 100 mg/d. Special Considerations Can be used alone or with other antiarthritic agents, but should not be used with tumor necrosis factor inhibitors.

Antimalarials Chloroquine Aralen Oral: Up to 4 mg/kg of lean body weight per day. Periodic ophthalmic exams recommended to check for retinal toxicity. Similar to chloroquine.



Oral: Up to 6.5 mg/kg of lean body weight per day. Oral: 1 mg/kg body weight per day; can be increased after 68 wk up to maximum dose of 2.5 mg/kg body weight. Oral: 1.52 mg/kg body weight per day; can be increased to a maximum daily dose of 3 mg/kg body weight. Oral: 2.5 mg/kg body weight per day; can be increased after 8 wk by 0.50.75 mg/kg body weight per day; dose can be increased after another 4 weeks to a maximum daily dose of 4 mg/kg body weight per day.



Relatively high toxicity; should be used cautiously in debilitated patients or patients with renal disease. Long-term use is limited because of potential for carcinogenicity.




Neoral, Sandimmune

May cause nephrotoxicity and gastrointestinal problems.

Gold compounds Auranofin Ridaura Oral: 6 mg/once each day or 3 mg BID May have a long latency (69 mo) before onset of benefits. Effects occur somewhat sooner than oral gold, but still has long delay (4 mo).



Intramuscular: 10 mg the 1st wk, 25 mg the 2nd and 3rd wk, then 2550 mg each wk until total dose is 1 g. Maintenance doses of 2550 mg every 24 wk can follow. Similar to aurothioglucose.

Gold sodium thiomalate


Similar to aurothioglucose.
(Continued on following page)


SECTION 4 Drugs Used to Treat Pain and Inflammation

Table 163
Drug Leflunomide


Trade Name Arava Usual Dosage Oral: 100 mg/d for the first 3 days; continue with a maintenance dosage of 20 mg/d thereafter. Special Considerations May decrease joint erosion/destruction with relatively few serious side effects; effects of longterm use remains to be determined. Often effective in halting joint destruction, but long-term use may be limited by toxicity.


Rheumatrex, others

Oral: 2.55 mg every 12 hr for total of 3 doses/wk or 10 mg once each week. Can be increased up to a maximum of 2025 mg/wk. Oral: 125 or 250 mg/d; can be increased to a maximum of 1.5 g/d. Oral: 0.51.0 g/d for the first week; dose can be increased by 500 mg each week up to a maximum daily dose of 23 g/d.


Cuprimine, Depen

Relatively high incidence of toxicity with long-term use. Relatively high toxicity; may produce serious hypersensitivity reactions and blood dyscrasias.



Tumor Necrosis Factor Inhibitors Adalimumab Humira Subcutaneous injection: 40 mg every week if used alone; 40 mg every other week if used in combination with other antiarthritic agents such as methotrexate. Subcutaneous injection: 25 mg twice each week. Slow intravenous infusion: 3 mg/ kg body weight. Additional doses at 2 and 6 weeks after first infusion, then every 8 weeks thereafter. Relatively low incidence of serious side effects compared to other immunosuppressants.



Similar to adalimumab.



Should be administered in combination with methotrexate.

Azathioprine (Imuran) is an immunosuppressant drug that is often used to prevent tissue rejection following organ transplants. Because of its immunosuppressant properties, this drug has been employed in treating

cases of severe, active rheumatoid arthritis that have not responded to other agents. Mechanism of Action. The mechanism of action of azathioprine in rheumatoid arthritis is not fully understood. This drug has been shown to impair the synthesis of DNA and RNA precursors, but it is

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis


unclear exactly how (or if) this is related to its immunosuppressant effects. Azathioprine can likewise inhibit lymphocyte proliferation, thereby impairing immune responses mediated by these cells.54 This action accounts for the immunosuppressant effects of this drug and for its ability to blunt the autoimmune responses that govern rheumatoid disease. Adverse Side Effects. Azathioprine is relatively toxic, with more frequent and more severe side effects than other DMARDs.97 The primary side effects include fever, chills, sore throat, fatigue, loss of appetite, and nausea or vomiting; these effects often limit the use of this drug.




Gold Therapy
Compounds containing elemental gold were among the first drugs identified as DMARDs (Fig. 161). Specific compounds such as aurothioglucose (Solganal) and gold sodium thiomalate (Myochrysine) have been used in the past and are usually administered by intramuscular injection. An orally active gold compound, auranofin (Ridaura), has also been developed and offers the advantage of oral administration.84 Auranofin is better tolerated than parenteral gold compounds in terms of adverse side effects.84 In the past, gold therapy was often used to arrest further progression of rheumatoid joint disease. Because safer and more effective agents have been developed, gold compounds are no longer used routinely in the treatment of rheumatoid arthritis, but are reserved for patients who fail to respond to other DMARDs.68 Mechanism of Action. Although the exact mechanism is not fully understood, gold compounds probably induce remission in patients with rheumatoid arthritis by inhibiting the growth and function of T cells and mononuclear phagocytes.27,84 These drugs accumulate in the lysosomes of macrophages and other synovial cells, thereby suppressing the action of key components in the cellular immune reaction inherent in this disease.84 A number of additional cellular effects have been noted (decreased lysosomal enzyme release, decreased prostaglandin E 2 production), and these effects may also contribute to the effectiveness of gold compounds in treating rheumatoid arthritis.84,111 Adverse Side Effects. Adverse effects are relatively common with gold therapy, with approximately one third of patients experiencing some form of toxic effect.84 The primary side effects caused by gold compounds are gastrointestinal distress (diarrhea, indigestion), irritation of the oral mucosa, and rashes and

Gold Sodium Thiomalate



FIGURE 161 Gold compounds used to treat rheumatoid arthritis.

itching of the skin.27,84 Other side effects include proteinuria, conjunctivitis, and blood dyscrasias (e.g., thrombocytopenia, leukopenia). As mentioned earlier, auranofin may be safer than parenteral gold compounds because it produces fewer cutaneous and potentially serious hematologic side effects, but auranofin tends to produce more gastrointestinal irritation than injected forms of gold.84

Leflunomide (Arava) is a relative newcomer to the antirheumatic drug arsenal. This drug helps decrease pain and inflammation in rheumatoid joint disease, and leflunomide has been shown to slow the formation of bone erosions in arthritic joints.19 Leflunomide is also fairly well tolerated by most patients and may produce beneficial effects fairly soon (1 month) after beginning treatment.57,105 This drug is therefore a po-


SECTION 4 Drugs Used to Treat Pain and Inflammation

tential alternative in people who have failed to respond to other DMARDs such as methotrexate.59,70 Mechanism of Action. Leflunomide acts primarily by inhibiting the synthesis of RNA precursors in lymphocytes.65,70 When stimulated, lymphocytes must radically increase their RNA synthesis to proliferate and become activated during the inflammatory response. Leflunomide blocks a key enzyme responsible for RNA synthesis, so that these lymphocytes cannot progress to a more activated state and cannot cause as much joint inflammation.58,107 Adverse Side Effects. Leflunomides primary side effects include gastrointestinal distress, allergic reactions (skin rashes), and hair loss.57 This drug can also affect the liver; liver function may need to be monitored periodically.19,70

Methotrexate (Folex, Rheumatrex) is an antimetabolite used frequently in the treatment of cancer (see Chapter 36). There is considerable evidence that this drug is also one of the most effective DMARDs.15,76 Methotrexate has been shown to slow the effects of rheumatoid arthritis as evidenced by decreased synovitis, decreased bone erosion, and less narrowing of the joint space.37 The therapeutic effects of methotrexate have also been reported to be equal to, or better than, other DMARDs such as oral gold or azathioprine, and methotrexate may offer an advantage in terms of a rapid onset.68,90 Hence, methotrexates popularity as a DMARD has increased during the past few years, and this drug is often the first DMARD used to treat rheumatoid arthritis in both adults and children.76 Mechanism of Action. The ability of methotrexate and similar anticancer drugs to impair DNA and RNA synthesis is well known (see Chapter 36). Methotrexate inhibits the synthesis of folic acid, thus inhibiting the formation of nucleoproteins that serve as DNA precursors.20 This action inhibits cellular replication by impairing the cells ability to produce new genetic material, an effect that helps attenuate tumor cell replication in cancer. Nonetheless, methotrexates effects on immune function and rheumatoid arthritis are somewhat unclear. This drug could affect immune function by inhibiting folic acid metabolism, thereby limiting the proliferation of lymphocytes and other cells that cause the autoimmune responses in rheumatoid disease. Methotrexate, however, also exerts other effects, including inhibition of inflammatory cytokines and stimulation of adenosine release.90 The effects on

adenosine release may be especially important because increased amounts of endogenous adenosine can inhibit various components of the immune response.92 Regardless of the exact mechanism, methotrexate has become a mainstay in the management of rheumatoid arthritis. Adverse Side Effects. Methotrexate is a relatively toxic drug, and a number of adverse side effects can occur.15,90 The primary problems involve the gastrointestinal tract and include loss of appetite, nausea, and other forms of gastrointestinal distress (including intragastrointestinal hemorrhage).90 Long-term methotrexate use in patients with rheumatoid arthritis has also been associated with pulmonary problems, hematologic disorders, liver dysfunction, and hair loss.15 These side effects often limit the use of methotrexate with rheumatoid arthritis, and most patients who stop using this drug do so because of an adverse side effect rather than a loss of effectiveness.104 Methotrexate does, however, offer a favorable benefit-to-risk ratio in many patients and has become one of the most commonly used DMARDs.

Penicillamine (Cuprimine), a derivative of penicillin, is officially classified as a chelating agent that is often used in the treatment of heavy metal intoxication (e.g., lead poisoning). In addition, this drug has been used in patients with severe rheumatoid arthritis, and seems to be as effective as other DMARDs such as methotrexate, sulfasalazine, and gold therapy.68,98 Penicillamine, however, tends to be substantially more toxic than other DMARDs, and is therefore used rarely in the treatment of specific patients with rheumatoid arthritis.68 Mechanism of Action. The basis for the antiarthritic effects of penicillamine is unknown. Reductions in serum immunoglobulin M-rheumatoid factor have been observed with penicillamine, and this drug has been shown to depress T-cell function.53 These and similar findings suggest that penicillamine works by suppressing the immune response in rheumatoid arthritis, but the exact mechanisms remain to be determined. Adverse Side Effects. Penicillamine is considered to be fairly toxic when compared with other DMARDs.68 Side effects that have been reported as occurring more frequently include fever, joint pain, skin rashes and itching, and swelling of lymph glands. Other adverse effects that may occur less frequently

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis


are bloody or cloudy urine, swelling of feet and legs, unusual weight gain, sore throat, and excessive fatigue.

Tumor Necrosis Factor Inhibitors

Several agents are now available that inhibit the action of tumor necrosis factor-alpha (TNF- ). TNF- is a small protein (cytokine) that is released from cells involved in the inflammatory response. TNF- seems to be a key chemical mediator that promotes inflammation and joint erosion in rheumatoid arthritis.83 Drugs that inhibit this chemical will therefore help delay the progression of this disease by decreasing TNF- s destructive effects.70 Drugs in this group include etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). These drugs are also referred to as biologic DMARDs because they affect the biologic response to a specific cytokine (TNF- ).68 Etanercept was the first biologic DMARD it was created by fusing human immunoglobulin (IgG) with an amino acid sequence that mimics the binding portion of the TNF receptor. TNF- recognizes the binding portion on the drug, attaches to this portion, and therefore cannot bind to the real TNF receptor. The two newer agents (infliximab and adalimumab) were developed using monoclonal antibody techniques. These techniques enable the drug to bind tightly to antigenic components on TNF- , thereby forming a drug-cytokine molecule that is too large to bind to the real TNF receptor. In addition, infliximab

and adalimumab can destroy cells that express TNF, thus further reducing the destructive effects of this cytokine. There is substantial evidence that TNF- inhibitors can retard the progression of inflammatory joint disease, and promote improvements in symptoms and quality-of-life with rheumatoid arthritis.13,51 These drugs are not typically used as the initial treatment, but can be used alone or added to other agents (e.g., methotrexate) if patients do not have an adequate response to other DMARDs.45,91 There is some concern about toxicity (see below), and these drugs must be given parenterally, usually by subcutaneous injection (twice each week for etanercept; every other week for adalimumab), or by slow intravenous infusion (every eight weeks for infliximab). Nonetheless, TNFinhibitors represent an important breakthrough in the drug treatment of rheumatoid arthritis. Mechanism of Action. As indicated, these agents bind selectively to TNF- (see Fig. 162).7,70,91 This action prevents TNF-a from binding to surface receptors located on other inflammatory cells. TNF is therefore unable to activate other inflammatory cells that cause inflammation and joint destruction in rheumatoid arthritis.70 Adverse Side Effects. Patients taking TNFinhibitors may be prone to upper respiratory tract infections and other serious infections, including sepsis.48,51,83 This increased risk of infection probably occurs because the drug inhibits a key component of the immune responsenamely, TNF- . These drugs

Etanercept TNFHuman IgG

Infliximab Adalimumab

Monoclonal Antibody

Joint Tissues

FIGURE 162 Schematic diagram illustrating the effects of tumor necrosis factor-alpha (TNF) inhibitors. Drugs such as etanercept, infliximab, and adalimumab attach directly to TNF- , thereby preventing this destructive cytokine from reaching joint tissues. See text for more details.


SECTION 4 Drugs Used to Treat Pain and Inflammation

are therefore contraindicated in people with infections, and administration should be discontinued if an infection develops. Other potential adverse responses include malignancy (e.g., lymphoma), liver disease, heart failure, lupuslike disease, irritation around the injection site, and demyelinating disorders that mimic multiple sclerosis.34,70,88 The incidence of these adverse effects, however, seems to be fairly low. For the most part, these drugs provide an acceptable risk-to-benefit ratio for most people with rheumatoid arthritis. Patients should, however, be screened carefully for any risk factors before beginning drug therapy, and should likewise be monitored periodically for any potential adverse reactions to these drugs.

Anakinra (Kineret) blocks the effects of interleukin-1 on joint tissues. Like TNF- , interleukin-1 is a cytokine that promotes inflammation and joint destruction in rheumatoid arthritis.23,36 By blocking interleukin-1 receptors on joint tissues, anakinra prevents the destructive events mediated by this cytokine. This drug appears to be moderately effective in limiting the progression of rheumatoid arthritis, and it is generally well tolerated.36 Hence, anakinra is another option that can be used alone or in combination with other DMARDs such as methotrexate.23 Mechanism of Action. As indicated, anakinra is an antagonist (blocker) that is specific for the interleukin1 receptor found on joint tissues, other tissues, and organs.23 By blocking this receptor, the drug prevents interleukin-1 from binding to this receptor and exerting destructive effects on joint tissues. Adverse Side Effects. Patients receiving anakinra may be more susceptible to bacterial infections and other infectious agents.70 This drug is administered via subcutaneous injection, and irritation at the injection site is fairly common, but is usually not severe. More serious systemic allergic reactions may occur in a small number of patients.70

patients with rheumatoid arthritis who have not responded to other measures.54 Sulfasalazine (Azulfidine), a drug that is typically used to treat inflammatory bowel disease, may also be helpful in treating rheumatoid arthritis because of its immunosuppressant effects.68 Cyclophosphamide (Cytoxan) is used primarily to treat cancer, but this agent can be used to suppress the immune system in severe cases of rheumatoid arthritis. In general, these drugs are more toxic and are usually reserved for patients who have not responded to more traditional DMARDs such as methotrexate. Drugs with immunosuppressant activity may also be used in combination with more traditional DMARDs to provide optimal benefits in certain patients. Combination drug therapy in rheumatoid arthritis is addressed in the next section.

DMARD Combinations Used in Rheumatoid Arthritis

There has been a great deal of interest in using several DMARDs simultaneously to achieve optimal effects in treating rheumatoid arthritis. The strategy of combination therapy is to attack the underlying disease process from several pharmacologic vantage points, much in the same way that combination therapies are used in other disorders such as hypertension (Chapter 21) and cancer (Chapter 36). Although the benefits of combining DMARDs have been questioned, most practitioners currently advocate a combination of two or more drugs so that optimal benefits can be achieved with a relatively low dose of each drug.42,68 Likewise, the best way to combine specific DMARDs is still being investigated, with various combinations of new and old DMARDs being studied for efficacy and toxicity.40,67 At present, methotrexate is typically the cornerstone of treatment, with other DMARDs added, depending on the needs of each patient.76 For example, a triple combination of methotrexate with hydroxychloroquine and sulfasalazine has been advocated as an effective treatment for many patients.39 In addition, some of the newer biologic agents such as the TNFinhibitors (etanercept, infliximab, adalamimab) and interleukin-1 inhibitors (anakinra) have been added to methotrexate to provide an effective combination in patients who have not responded to use of only one drug.31,68 The drawback of combination therapy is, of course, the potential for increased toxicity and drug interactions when several DMARDs are used simulta-

Other DMARDs
Because of the autoimmune basis of rheumatoid arthritis, various other drugs that affect the immune response are used on a limited basis. For instance, cyclosporine (Sandimmune), an immunosuppressant agent that is used to prevent rejection of organ transplants (see Chapter 37), is sometimes used to treat

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis


neously.68 This fact is understandable, considering that many DMARDs have a relatively high risk of toxicity when used alone, and combining these drugs will certainly increase the risk of adverse drug reactions. There is, however, evidence that the incidence of side effects is not necessarily greater when DMARD combinations are used compared with a single drug such as methotrexate.68,99 Hence, combination therapy continues to gain acceptance, and the use of two or three DMARDs early in the course of the disease may provide patients with the best hope for halting the progression of rheumatoid arthritis.99 Continued research will hopefully lend additional insight to the best way that DMARDs can be combined to safely and effectively treat patients with rheumatoid arthritis.

Dietary Implications for Rheumatoid Arthritis

There is an ongoing search for other pharmacologic and nonpharmacologic interventions that can help arrest the progression of rheumatoid joint disease. There is some evidence, for example, that dietary manipulation can alleviate the symptoms of rheumatoid arthritis.72 Diets that are high in fish oil and certain fatty acids (e.g., gammalinolenic acid) have been advocated for patients with rheumatoid arthritis because these diets may supply precursors that enhance the biosynthesis of certain endogenous anti-inflammatory and immunosuppressant compounds.81,85 Foods that have antioxidant properties (e.g., fruits, vegetables) may also have beneficial effects in people with rheumatoid arthritis.81 On the other hand, diets that are rich in meat and protein may exacerbate rheumatoid arthritis and similar inflammatory diseases.21 Hence, dietary changes used in combination with drug therapy may provide additional benefits for some people with rheumatoid arthritis.

Osteoarthritis far exceeds rheumatoid arthritis as the most common form of joint disease. The prevalence of osteoarthritis increases with age.2 Approximately 50 to 80 percent of people aged 65 years have osteoarthritis to some extent, and virtually everyone over 75 years has some degree of osteoarthritic joint disease.14 In contrast to rheumatoid joint disease, osteoarthritis does not seem to be caused by an immune response,

but rather an intrinsic defect in the joint cartilage. This defect causes a slow, progressive deterioration of articular cartilage that is accompanied by degenerative bony changes, including thickening of the subchondral bone, creation of subchondral bone cysts, and formation of large bony protrusions (osteophytes) at the joint margins.14 Osteoarthritis typically occurs in large weight-bearing joints such as the knees and hips, as well as some of the smaller joints in the hands and feet.18 Patients are described as having primary osteoarthritis when there is no apparent reason for the onset of joint destruction; in secondary osteoarthritis, a factor such as previous joint trauma, infection, or metabolic disease is responsible for triggering articular changes.14 Obesity, genetic susceptibility, and joint vulnerability (malalignment, weakness, and so forth) have also been implicated as predisposing factors in osteoarthritis.30 Clearly, osteoarthritis is a different form of joint disease than rheumatoid arthritis. Hence, treatment of these conditions also differs somewhat. As discussed previously, rheumatoid arthritis is characterized by a severe inflammatory response that is perpetuated by a cellular immune reaction. Thus, drug therapy in rheumatoid disease consists of agents that are focused on directly relieving these inflammatory symptoms (i.e., NSAIDs or glucocorticoids) or drugs that attempt to arrest the cellular immune response that causes this inflammation (DMARDs). Treatment of joint inflammation is not a major focus of drug therapy in osteoarthritis, however. A mild inflammatory synovitis does occur in osteoarthritis, but this is secondary to the articular damage inherent to this disease.14 Also, drug therapy represents one of the primary interventions in rheumatoid arthritis, whereas treatment of osteoarthritis should be focused more directly on nonpharmacologic measures such as physical therapy, weight loss, and joint replacement in the advanced stages of this disease.93 Hence, drug therapy in osteoarthritis is focused primarily on helping patients manage their pain and maintain an active lifestyle. When joint pain begins to be a problem, simple analgesics such as acetaminophen and NSAIDs have been the major form of drug therapy. Newer pharmacologic strategies are also emerging that attempt to slow or reverse the pathologic changes in osteoarthritis. These newer strategies use diseasemodifying osteoarthritic drugs (DMOADs) rather than drugs that treat only the symptoms of osteoarthritis.28,90 Two types of DMOADs will be addressed: drugs that attempt to directly improve the viscosity


SECTION 4 Drugs Used to Treat Pain and Inflammation

and function of synovial fluid (viscosupplementation) and agents that serve as precursors to the normal constituents of joint tissues (glucosamine and chondroitin sulfate).

Acetaminophen and NSAIDs

Acetaminophen is often the first drug used to treat osteoarthritis.9,10 As indicated in Chapter 15, acetaminophen is as effective as NSAIDs in controlling pain, but acetaminophen does not have anti-inflammatory effects. The lack of anti-inflammatory effects is of less concern when acetaminophen is used in osteoarthritis because the inflammatory symptoms are milder. Acetaminophen is therefore successful in reducing pain, and because this drug does not cause gastric irritation, acetaminophen is often considered the drug of choice in mild-to-moderate osteoarthritis.9,108 Hence, acetaminophen provides a relatively safe and effective form of analgesia for patients with osteoarthritis, especially when this drug needs to be administered for long periods of time.9 NSAIDs are also used for the symptomatic treatment of pain in osteoarthritis.10,75 These drugs are used primarily for their analgesic properties, although the anti-inflammatory effects of NSAIDs can help control the mild synovitis that typically occurs in advanced osteoarthritis secondary to joint destruction.75 If the primary goal is pain reduction, however, NSAIDs do not provide any advantage over acetaminophen. As indicated earlier, acetaminophen is often a better choice than traditional NSAIDs because most NSAIDs cause gastric irritation. The newer COX-2 selective NSAIDs (see Chapter 15) do not appear to cause as much gastric irritation as other NSAIDs, and these COX-2 drugs may be a valuable alternative to acetaminophen and traditional NSAIDs in the longterm treatment of osteoarthritis. COX-2 drugs, however, may increase the risk of serious cardiovascular problems (heart attack, stroke), and patients should be screened carefully for cardiovascular risk factors before beginning treatment with COX-2 drugs.44 Regardless of the exact drug used, there is no doubt that the analgesia produced by NSAIDs or acetaminophen plays a valuable role in the management of osteoarthritis. These drugs allow the patient to maintain a more active lifestyle and to participate in various activities, including exercise programs and other forms of physical therapy and occupational therapy. However, these drugs do not alter the progressive course of joint destruction and osteoarthritic changes. There is

preliminary evidence, in fact, that some of the NSAIDs may actually impair bone healing following fractures or surgery, but their effects on cartilage formation and soft tissue repair remain unclear (see Chapter 15).26,46 At the present time, however, acetaminophen and NSAIDs remain the cornerstone of the pharmacologic treatment of joint pain in osteoarthritis.

Viscosupplementation is a clinical procedure that is being used increasingly in the treatment of osteoarthritis. This technique uses a substance known as hyaluronan to restore the lubricating properties of synovial fluid in osteoarthritic joints.6,41 Hyaluronan is a polysaccharide that can be injected into an arthritic joint to help restore the normal viscosity of the synovial fluid.6 This treatment helps reduce joint stresses, thus limiting the progression of articular destruction seen in osteoarthritis.106 Viscosupplementation has therefore been shown to reduce pain and improve function in osteoarthritis.1,95 When used to treat osteoarthritis, viscosupplementation typically consists of 2 to 10 weekly injections of hyaluronan Hyalgan, Synvisc, others. Patients often experience a decrease in pain within days after injection, and pain continues to diminish within the first weeks after treatment. Duration of relief is variable, but most patients who respond to viscosupplementation experience beneficial effects for 6 months to 1 year after a series of injections.74 Hence, viscosupplementation may temporarily attenuate the progressive changes in joint structure and function typically seen in osteoarthritis. Although these benefits are relatively transient, viscosupplementation can delay the need for more invasive surgical treatments such as joint replacement. This intervention is also tolerated fairly well, although a pseudoseptic reaction that produces local pain and swelling may occur.41,106 Future clinical studies will be needed to determine how viscosupplementation can be used most effectively in the comprehensive treatment of people with osteoarthritis.

Glucosamine and Chondroitin Sulfate

It has been suggested that dietary supplements such as glucosamine and chondroitin sulfate may help protect articular cartilage and halt or reverse joint degeneration in osteoarthritis. These two compounds are key ingredients needed for the production of several

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis


components of articular cartilage and synovial fluid, including glycosaminoglycans, proteoglycans, and hyaluronic acid.71,112 It seems reasonable that increased amounts of these ingredients should facilitate the repair of joint tissues, improve synovial fluid viscosity, and help restore joint function in conditions like osteoarthritis. Hence, several products containing glucosamine, or glucosamine combined with chondroitin sulfate, are currently available as nonprescription dietary supplements. These supplements typically contain oral dosages of 1500 mg/d glucosamine and 1200 mg/d chondroitin sulfate.82 Several recent studies suggest that chondroitin and glucosamine supplements can decrease pain and improve function in some patients with osteoarthritis.47,62,64 Radiographic studies also indicate that these supplements can reduce joint space narrowing in knee osteoarthritis, thus providing some protective effects on joint structure.78,82 These benefits may not occur in all patientspatients with a high rate of cartilage tur-

nover may be more likely to experience positive effects because these supplements will provide the necessary substrates to sustain this turnover and maintain joint integrity.22 Consequently, it appears that glucosamine and chondroitin supplements are certainly worth a trial for many patients with osteoarthritis. Some gastrointestinal problems may occur, but these supplements are usually well tolerated. Although these supplements are available over-the-counter in the United States, people with osteoarthritis should consult their physician and pharmacist before self-administration. Likewise, patients should be educated on the proper dosage, and should be reminded that these products may need to be consumed for several weeks or months before beneficial effects become apparent. Long-term studies on the effects of these supplements are currently being conducted, and clinicians should try to stay abreast of any new information about the potential benefits of glucosamine and chondroitin.

Special Concerns for Antiarthritic Drug Therapy in Rehabilitation Patients

Drugs used to treat rheumatoid arthritis and osteoarthritis often play a vital role in permitting optimal rehabilitation of patients with joint disease. By decreasing pain and inflammation, these drugs help facilitate a more active and vigorous program of exercise and functional activity. Some drugs, such as the disease-modifying drugs used in rheumatoid arthritis and osteoarthritis, appear to be able to impair or even halt the progression of joint destruction. This may enable the therapist to help restore muscle strength and joint function rather than simply employ a program of maintenance therapy during a steady downward progression in patients with arthritis. The influence of antiarthritic drugs on the rehabilitative process depends primarily on the type of drugs used. Beginning with the NSAIDs, there is little concern for adverse effects on physical therapy procedures. These drugs are relatively safe and are not usually associated with the type of side effects that will directly influence the physical rehabilitation of people with rheumatoid arthritis or osteoarthritis. If glucocorticoids are used, the therapist must be aware of adverse side effects; in particular, the catabolic effects of these agents on supporting tissues (muscle, tendon, bone, skin) must be considered. Range-of-motion and strengthening programs must be used judiciously to avoid fractures and soft-tissue injuries. Care must also be taken to prevent skin breakdown, especially when splints and other protective orthotic devices are employed. The disease-modifying agents used in rheumatoid arthritis are associated with a number of side effects that could influence rehabilitation. Some of these drugs, such as the gold compounds and methotrexate, may cause headache and nausea, which may be bothersome during the therapy session. Joint pain and swelling may also occur with drugs such as methotrexate and peniContinued on following page


SECTION 4 Drugs Used to Treat Pain and Inflammation

cillamine, and these effects may also become a problem during rehabilitation. A variety of other side effects can occur, depending on the particular DMARD being used and the sensitivity of the patient. Therapists should be aware of any changes in patient response, not only when a new drug is being started but also during the prolonged use of DMARDs. Finally, the use of DMOADs (viscosupplementation, glucosamine, chondroitin) to restore joint function in osteoarthritis is fairly new, and it is not clear if these techniques will have any side effects that will have a direct impact on physical rehabilitation. Likewise, it remains to be seen if there are any rehabilitation techniques (exercise, physical agents) that could enhance the effectiveness of DMOADs. It is hoped that these techniques will work synergistically with physical therapy to improve function in patients with osteoarthritic joints.

Rheumatoid Arthritis
Brief History. A.T., a 75-year-old woman, was diagnosed with rheumatoid joint disease several years ago. She is currently being seen three times each week in physical therapy as an outpatient for a program of paraffin and active exercise to her wrists and hands. Resting splints were also fabricated for both hands, and these are worn at night to prevent joint deformity. The patient was also instructed in a home exercise program to maintain joint mobility in both upper extremities. Pharmacologic management in this patient originally consisted of NSAIDs, beginning with aspirin and later switching to ibuprofen. Six months ago, she was also placed on auranofin (Ridaura), which was instituted in an attempt to halt the progressive arthritic changes. This orally administered gold compound was given at a dosage of 3 mg twice each day. Problem/Influence of Medication. The combination of an NSAID and a disease-modifying drug, along with the physical therapy program, seemed to be helping to decrease the patients pain and joint stiffness. However, she began to develop skin rashes and itching on her arms and legs. The therapist noticed this while preparing the patient for her paraffin treatment. It seemed that these rashes might be occurring as a side effect of the auranofin. The therapist brought this to the attention of the physician, who concurred that this was probably a side effect of the gold therapy. Decision/Solution. The patient was temporarily removed from auranofin therapy to see if this skin reaction would subside. In the interim, the therapist discontinued paraffin so that the rashes and itching would not be exacerbated. To continue to provide gentle heat, a warm whirlpool (100 F) was substituted for the paraffin bath. Also, the night splints were temporarily discontinued to prevent irritation to the affected areas. After 2 weeks, the skin rashes had virtually disappeared, and the original physical therapy program was resumed. After another week, the physician restarted DMARD therapy in the form of low dose methotrexate combined with etanercept (Enbrel). This combination was intended to provide a more comprehensive antiarthritic regimen, while reducing the chance of the allergic response that is common with gold compounds. No other adverse effects were noted, and the patient continued to notice improvements in her arthritic condition.

Rheumatoid arthritis and osteoarthritis represent two distinct forms of joint disease that can produce devastating effects on the structure and function of synovial joints. Fortunately, management of these conditions has improved substantially through advancements in drug therapy. Rheumatoid arthritis can be treated pharmacologically with NSAIDs, glucocorticoids, and various DMARDs. NSAIDs, including aspirin, repre-

sent the primary form of drug therapy in the early stages of this disease, and these drugs are often used in conjunction with other drugs as the arthritic condition increases in severity. Glucocorticoids are often effective in decreasing the joint inflammation typically found in rheumatoid arthritis, but long-term use of these agents is limited because of their toxic effects. Disease-modifying drugs can slow or halt the progressive nature of rheumatoid arthritis by suppressing the immune response inherent in this disease. Although

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis


there is some concern about the efficacy and safety of these drugs, DMARDs have been a welcome addition to the rather limited arsenal of drugs used to treat rheumatoid arthritis. Drug treatment of osteoarthritis differs somewhat from that of rheumatoid arthritis, with management of pain by using NSAIDs and acetaminophen constituting the major forms of drug therapy. A newer technique known as viscosupplementation has also been used to help restore the lubricating properties of

the synovial fluid in osteoarthritic joints. Dietary supplements containing glucosamine and chondroitin sulfate may also help provide constituents that protect joint structure and function, and some people with osteoarthritis have benefited from their long-term use. In any event, drug therapy along with nonpharmacologic measures such as physical therapy can provide an effective way of dealing with the potentially devastating effects of rheumatoid arthritis and osteoarthritis.

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SECTION 4 Drugs Used to Treat Pain and Inflammation 50. Jacobs JW, Geenen R, Evers AW, et al. Short term effects of corticosteroid pulse treatment on disease activity and the wellbeing of patients with active rheumatoid arthritis. Ann Rheum Dis. 2001;60:6164. 51. Keystone EC. Safety of biologic therapiesan update. J Rheumatol Suppl. 2005;74:812. 52. Kirwan JR. Effects of long-term glucocorticoid therapy in rheumatoid arthritis. Z Rheumatol. 2000;59 (suppl 2):II, 8589. 53. Klaassen CD. Heavy metals and heavy-metal antagonists. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 54. Krensky AM, Strom TB, Bluestone J.: Immunomodulators: immunosuppressive agents, tolerogens, and immunostimulants. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 55. Kvien TK. Epidemiology and burden of illness of rheumatoid arthritis. Pharmacoeconomics. 2004;22 (suppl 2):112. 56. Lee SJ, Kavanaugh A. Pharmacological treatment of established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2003;17:811829. 57. Li EK, Tam LS, Tomlinson B. Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004; 26:447459. 58. Lorenz HM. T-cell-activation inhibitors in rheumatoid arthritis. BioDrugs. 2003;17:263270. 59. Maddison P, Kiely P, Kirkham B, et al. Leflunomide in rheumatoid arthritis: recommendations through a process of consensus. Rheumatology. 2005;44: 280286. 60. Marmor MF. Hydroxychloroquine at the recommended dose ( or 6.5 mg/kg/day) is safe for the retina in patients with rheumatoid arthritis and systemic lupus erythematosus. Clin Exp Rheumatol. 2004;22: 143144. 61. Martel-Pelletier J, Pelletier JP, Fahmi H. Cyclooxygenase-2 and prostaglandins in articular tissues. Semin Arthritis Rheum. 2003;33:155167. 62. Matheson AJ, Perry CM. Glucosamine: a review of its use in the management of osteoarthritis. Drugs Aging. 2003;20:10411060. 63. Mavrikakis I, Sfikakis PP, Mavrikakis E, et al. The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine: a reappraisal. Ophthalmology. 2003;110:13211326. 64. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis.JAMA. 2000;283:14691475. 65. Miceli-Richard C, Dougados M. Leflunomide for the treatment of rheumatoid arthritis. Expert Opin Pharmacother. 2003;4:987997. 66. Morrow JD, Roberts LJ. Lipid-derived autacoids: eicosanoids and platelet-activating factor. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 67. Mullan RH, Bresnihan B. Disease-modifying antirheumatic drug therapy and structural damage in early

30. Felson DT. Risk factors for osteoarthritis: understanding joint vulnerability. Clin Orthop Relat Res. 2004;427: (suppl):S16S21. 31. Finesilver AG. Newer approaches to the treatment of rheumatoid arthritis. WMJ. 2003;102:3437. 32. Firestein GS, Corr M. Common mechanisms in immune-mediated inflammatory disease. J Rheumatol Suppl. 2005;73:813; discussion 2930. 33. Fitzpatrick FA. Cyclooxygenase enzymes: regulation and function. Curr Pharm Des. 2004;10:577588. 34. Fleischmann RM, Iqbal I, Stern RL. Considerations with the use of biological therapy in the treatment of rheumatoid arthritis. Expert Opin Drug Saf. 2004;3: 391403. 35. Fox, RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum. 1993;23(suppl 1):8291. 36. Furst DE. Anakinra: review of recombinant human interleukin-I receptor antagonist in the treatment of rheumatoid arthritis. Clin Ther. 2004;26:19601975. 37. Furst, DE. The rationale use of methotrexate in rheumatoid arthritis and other rheumatic diseases. Br J Rheumatol. 1997;36:11961204. 38. Gabriel SE. The epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am. 2001;27:269281. 39. Garrood T, Scott DL. Combination therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis. BioDrugs. 2001;15:543561. 40. Geletka R, St Clair EW. Treatment of early rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2003;17: 791809. 41. Goldberg VM, Coutts RD. Pseudoseptic reactions to hylan viscosupplementation: diagnosis and treatment. Clin Orthop Relat Res. 2004;419:130137. 42. Gossec L, Dougados M. Combination therapy in early rheumatoid arthritis.Clin Exp Rheumatol. 2003; 21(suppl 31):S174S178. 43. Gotzsche PC, Johansen HK. Short-term low-dose corticosteroids vs placebo and nonsteroidal antiinflammatory drugs in rheumatoid arthritis. Cochrane Database Syst Rev. 2004;CD000189. 44. Grainger R, Cicuttini FM. Medical management of osteoarthritis of the knee and hip joints. Med J Aust. 2004;180:232236. 45. Haraoui B. The anti-tumor necrosis factor agents are a major advance in the treatment of rheumatoid arthritis. J Rheumatol Suppl. 2005;72:4647. 46. Harder AT, An YH. The mechanisms of the inhibitory effects of nonsteroidal anti-inflammatory drugs on bone healing: a concise review. J Clin Pharmacol. 2003;43:807815. 47. Hungerford DS, Jones LC. Glucosamine and chondroitin sulfate are effective in the management of osteoarthritis. J Arthroplasty. 2003;18(suppl 1):59. 48. Hyrich KL. Assessing the safety of biologic therapies in rheumatoid arthritis: the challenges of study design. J Rheumatol Suppl. 2005;72:4850. 49. Issa SN, Ruderman EM. Damage control in rheumatoid arthritis. Hard-hitting, early treatment is crucial to curbing joint destruction. Postgrad Med. 2004;116: 1416, 2124.

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis rheumatoid arthritis. Clin Exp Rheumatol. 2003;21 (suppl 31):S158S164. ODell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med. 2004;350:25912602. Olson JC. Juvenile idiopathic arthritis: an update. WMJ. 2003;102:4550. Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med. 2004;350:21672179. Owens S, Wagner P, Vangsness CT, Jr. Recent advances in glucosamine and chondroitin supplementation. J Knee Surg. 2004;17:185193. Pattison DJ, Harrison RA, Symmons DP. The role of diet in susceptibility to rheumatoid arthritis: a systematic review. J Rheumatol. 2004;31:13101319. Petersson IF, Jacobsson LT. Osteoarthritis of the peripheral joints. Best Pract Res Clin Rheumatol. 2002;16:741760. Peyron, JG. Intraarticular hyaluronan injections in the treatment of osteoarthritis: state-of-the-art review. J Rheumatol. 1993;39:1015. Pincus T. Clinical evidence for osteoarthritis as an inflammatory disease. Curr Rheumatol Rep. 2001;3: 524534. Pincus T, Yazici Y, Sokka T, et al. Methotrexate as the anchor drug for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol. 2003;21(suppl 31): S179S185. Porter DR, Sturrock RD. Fortnightly review: medical management of rheumatoid arthritis. BMJ. 1993;307: 425428. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251256. Reiff AO. Juvenile arthritis. In: Rakel RE, Bope ET, eds. Conns Current Therapy 2005. New York: Elsevier Saunders; 2005. Reiff AO. Developments in the treatment of juvenile arthritis. Expert Opin Pharmacother. 2004;5:14851496. Rennie KL, Hughes J, Lang R, Jebb SA. Nutritional management of rheumatoid arthritis: a review of the evidence. J Hum Nutr Diet. 2003;16:97109. Richy F, Bruyere O, Ethgen O, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med. 2003;163:15141522. Roberts L, McColl GJ. Tumour necrosis factor inhibitors: risks and benefits in patients with rheumatoid arthritis. Intern Med J. 2004;34:687693. Roberts LJ, Morrow JD. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Hardman JG, et al, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. Ruxton C. Health benefits of omega-3 fatty acids. Nurs Stand. 2004;18:3842. Saag KG. Glucocorticoid use in rheumatoid arthritis. Curr Rheumatol Rep. 2002;4:218225. Saklatvala J, Dean J, Clark A. Control of the expression of inflammatory response genes. Biochem Soc Symp. 2003;70:95106.


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Patient-Controlled Analgesia
Patient-controlled analgesia (PCA) was first introduced into clinical practice in the early 1980s as an alternative way to administer analgesic medications. The basic principle behind PCA is that the patient can self-administer small doses of the drug (usually an opioid) at relatively frequent intervals to provide optimal pain relief.32 These small doses are typically delivered intravenously or into the spinal canal by some type of machine (pump) that is controlled by the patient. Patient-controlled analgesia has several advantages over more traditional dosing regimens. In particular, PCA systems often provide equivalent or increased analgesic effects with a lower incidence of side effects while using less of the drug.9,32 This fact has generated a great deal of interest and increased use of PCA in a variety of clinical situations. For instance, PCA systems have been used to help manage acute pain following surgery, and PCAs have also been used to treat pain in patients with cancer and other conditions associated with chronic pain.10,19 Hence, PCA continues to gain acceptance as an optimal method for treating pain. Because PCA is used extensively to treat acute and chronic pain, rehabilitation specialists should be aware of some of the fundamental principles governing PCA. This chapter begins by discussing the basic concepts and strategies of PCA, followed by some of its practical aspects, including the types of analgesics used, the possible routes of administration, and the types of machines used to administer the drugs. An indication of why PCA is often clinically superior to more traditional methods of analgesia is then presented. Finally, potential problems associated with PCA and the specific ways that PCA can affect patients receiving physical therapy and occupational therapy are discussed. It is hoped that this will provide the reader with a better understanding of why PCA systems are often a preferred method of managing pain in contemporary practice.

Pharmacokinetic Basis for PCA

To provide optimal management of pain, analgesic drugs should be delivered into the bloodstream or other target tissues (epidural space, within joints, and so forth) in a predictable and fairly constant manner. The goal is to maintain drug levels within a fairly welldefined range, or therapeutic window.32 Such a therapeutic window for systemic (intravenous) dosages is represented schematically by the shaded area in Figure 171. If drug levels are below this window, the analgesic is below the minimum analgesic concentration, and the patient is in pain. Drug levels above the window may produce adequate analgesia but may also produce side effects such as sedation. The traditional method of administering analgesics is to give relatively large doses with relatively large time intervals between each dosage. For instance, opioid analgesics are typically injected intramuscularly every 3 to 4 hours to manage severe pain, thus creating large fluctuations in the amount of drug present in the body. The dark solid lines in Figure 171 illustrate these large fluctuations. As illustrated in Figure 171, this traditional method of administration is associated with long periods of time when the drug concentration falls below the therapeutic window, allowing pain to occur, or above the therapeutic window, causing sedation. Figure 171 also illustrates why PCA systems are better at maintaining drug levels within the therapeutic (analgesic) window. Systems using some form of PCA deliver small doses of the analgesic on a relative237


SECTION 4 Drugs Used to Treat Pain and Inflammation

Analgesic Drug Concentration

minimal analgesic concentration dose dose

minimal analgesic concentration dose



1000 Time (hours)



FIGURE 171 Pharmacokinetic model for PCA using opioid drugs. Conventional intramuscular injection is indicated by the long solid lines, PCA is indicated by the short dashed lines, and the therapeutic window for analgesia is indicated by the shaded area. (From Ferrante, et al. Anesth Analg. 1988;67: 457461; with permission.)

ly frequent basis, as indicated by the dashed lines. Drug levels are maintained within the analgesic range; there are shorter periods of time when the drug concentration falls below the therapeutic window (i.e., below the shaded area), and there is virtually no time when side effects occur because the concentration rises above the therapeutic window. Hence, analgesia can be achieved more effectively with a reduced incidence of side effects.

analgesic to the therapeutic window, as illustrated by the shaded area in Figure 171.

Demand Dose
The amount of drug that is self-administered by the patient each time he or she activates the PCA delivery mechanism is known as the demand dose. The magnitude of these doses for some commonly used opioid analgesics is listed in Table 171.

PCA Dosing Strategies and Parameters

The fact that PCA enables the patient to self-deliver small doses of the analgesic at frequent intervals illustrates the need for specific dosing parameters that control the amount and frequency of analgesic administration. Several terms are used to describe these parameters and indicate each parameters role in safeguarding against excessive drug delivery.34,38 The basic terms that describe PCA dosing strategies are indicated below.

Lockout Interval
The minimum amount of time allowed between each demand dose is called the lockout interval. After the patient self-administers a dose, the PCA delivery system will not deliver the next dose until the lockout interval has expired. Typical lockout intervals for commonly used opioids are listed in Table 171.

1- and 4-Hour Limits

Some PCA systems can be set to limit the total amount of drug given in a 1- or 4-hour period. The use of these parameters is somewhat questionable, however, because other parameters such as the demand dose and lockout interval automatically limit the total amount of drug that can be given in a specific period of time.

Loading Dose
A single large dose is given initially to establish analgesia. This loading dose is used to bring levels of the


Analgesia Sedation

Chapter 17 Patient-Controlled Analgesia


Table 171


Demand Dose 0.10.2 mg 0.030.1 mg 1020 g 0.050.25 mg 525 mg 0.52.5 mg 0.52.5 mg 15 mg 0.20.4 mg 530 mg 0.20.5 g Lockout Interval (min) 58 820 310 510 510 820 510 515 810 515 310

Drug (Concentration) Alfentanil (0.1 mg/mL) Buprenorphine (0.03 mg/mL) Fentanyl (10 g/mL) Hydromorphone (0.2 mg/mL) Meperidine (10 mg/mL) Methadone (1 mg/mL) Morphine (1 mg/mL) Nalbuphine (1 mg/mL) Oxymorphone (0.25 mg/mL) Pentazocine (10 mg/mL) Sufentanil (.2 g/mL)
Source: Ready,38 p 2328, with permission.

Background Infusion Rate

In some patients, a small amount of the analgesic is infused continuously to maintain a low, background level of analgesia. Demand doses are superimposed on the background infusion whenever the patient feels an increase in pain (e.g., the so-called breakthrough pain that may occur when the patient coughs or changes position). The use of background infusion basically combines the technique of continuous infusion with PCA, which may provide optimal analgesia with minimal side effects.38 Background infusion, for example, can maintain adequate analgesia even when patients are asleep or otherwise unable to activate the pump manually. Nonetheless, routine use of background infusion has been questioned, especially when opioids are administered systemically (intravenously) by PCA. It appears that background infusions may not provide any additional analgesic benefits in most patients, but they can lead to an increased risk of side effects such as respiratory depression because patients ultimately receive a larger total amount of opioid (i.e., the background infusion plus the demand doses).8,34 Hence, background infusion rates have been discouraged for

most patients, but may still be used in specific cases such as patients who need larger amounts of opioids to control pain, especially during sleep.34

Successful Versus Total Demands

Successful demands occur when the patient activates the PCA delivery system and actually receives a demand dose of the drug. Demands made during the lockout interval are not considered successful, but are added to the number of successful demands to indicate the total demands. A large number of unsuccessful demands may indicate that the PCA parameters are not effective in providing adequate analgesia. Therefore, most PCA systems record the number of total demands so that the demand dose can be adjusted if a large number of unsuccessful demands are being made.

Types of Analgesics Used for PCA

Opioid analgesics (see Chapter 14) are the primary medications used during PCA.9 Opioids such as morphine, meperidine, tramadol, fentanyl, and fentanyl


SECTION 4 Drugs Used to Treat Pain and Inflammation

derivatives (alfentanil, remifentanil) are powerful analgesics that act primarily on the spinal cord and brain to inhibit the transmission and perception of nociceptive impulses. Opioids must be used cautiously because these drugs can cause serious side effects and have the potential for patient overdose. As explained earlier, PCA often provides a safer and more effective way to administer these powerful drugs by preventing large fluctuations in plasma opioid levels. Likewise, a number of nonopioid analgesics have been combined with opioids during systemic (intravenous) PCA to decrease the amount of opioid needed for adequate analgesia. This opioid sparing effect can be achieved by combining morphine or other opioids with ketorolac (an NSAID; see Chapter 15), ketamine (an anesthetic agent; see Chapter 11), or droperidol (an antipsychotic; see Chapter 8).15,33,43 Alternatively, a very low dose of an opioid receptor antagonist (blocker) such as naloxone (see Chapter14) can also be administered along with the opioid during PCA. Preliminary evidence suggests that a low dosage of the opioid antagonist may block certain opioid side effects (nausea, pruritus) while still allowing an adequate level of analgesia.11,36 Local anesthetics such as bupivacaine and ropivacaine have also been used during PCA (see Chapter 12). These drugs, which block transmission along afferent sensory neurons, can be administered epidurally to block sensation at the spinal cord level. Local anesthetics are often administered when an epidural PCA is used during labor and childbirth.23 These drugs have also been mixed with opioids to provide optimal epidural PCA during labor or following surgery.2,4,25 Local anesthetics can also be applied to a specific site such as the subacromial space or around a specific peripheral nerve. This technique, known as patient controlled regional anesthesia (PCRA), is discussed later. Hence, local anesthetics serve as an alternative or adjunct to opioids during several types of PCA.

(IV) line. The catheter is then connected to a PCA pump (see later), and small intermittent doses of the analgesic are administered through the catheter and delivered directly into the systemic circulation. This technique is often effective in allowing the patient to regulate his or her level of analgesia for a short period of time (e.g., for the first few days after surgery). When PCIA is needed for longer periods, a catheter can be implanted surgically in a large central vein, with the tip of the catheter advanced to the right atrium of the heart. The catheter is then tunneled through subcutaneous tissues and brought out through the patients skin to allow administration of PCA. Alternatively, the catheter can be connected to a small container known as an access port, which is implanted subcutaneously within the patients body (Fig. 172). This type of catheter-port system is used to provide a method of IV drug delivery that is located primarily within the patients body. Injections can be made through the skin and into the port through a self-sealing silicone rubber septum located on the port. When these ports are used during PCA, the external PCA source is connected to the port via a special (Huber) needle that is inserted through the skin and into the port (see Fig. 172). The analgesic drug is then given from the PCA pump through a catheter into the port and ultimately into the systemic circulation. This provides an effective way of getting small, frequent doses of the drug into the bloodstream with less risk of infection or intravenous catheter displacement. This type of PCA-port delivery also enables the

Self-sealing septum

Skin line

Administration Routes During PCA

Intravenous PCA
Patient controlled intravenous analgesia (PCIA) is perhaps the simplest and most common method of PCA administration. PCIA is typically administered by inserting a needle into a peripheral vein, and then connecting the needle to a catheter or intravenous

Suture Fluid flows


FIGURE 172 Schematic representation of an implantable vascular access port that can be used with PCA. The port can be connected to a PCA pump via a percutaneous needle, and a catheter leads from the port to a large central vein. (From Knox LS. Crit Care Nurse. 1987;7:71; with permission.)

Chapter 17 Patient-Controlled Analgesia


patient to be disconnected from the PCA delivery system for short periods of time by removing the needle from the port. This allows the patient to bathe or get dressed without risking damage to the indwelling port-IV system.17

Epidural PCA
Patient controlled epidural analgesia (PCEI) is achieved by administering drugs directly into the area outside of the membranes (meninges) surrounding the spinal cord.9 This is typically done by inserting a small catheter so that the tip of the catheter lies in the epidural space at a specific level of the spinal cord (Fig. 173). Alternatively, the tip of the catheter can be placed in the subarachnoid spacethis type of delivery is known as spinal or intrathecal administration. That is, the drug is delivered into the space between the middle (arachnoid) layer of the meninges and the inner (pia mater) meningeal membrane (intrathecal

Insertion Site - Epidural - Intrathecal Exit Site

means within a sheath; see Chapter 2). Although intrathecal administration can be used in certain situations, the epidural route seems to be the preferred method during PCA because it is safer and there is less risk of damaging the meninges. If PCEA is intended for short-term use, the catheter can be externalized through the skin on the midline of the patients back and held in place by surgical tape. For long-term use, the catheter is often tunneled through the subcutaneous tissues in the patients abdominal wall, after which the catheter can either be brought out through the skin on the patients side (see Fig. 173) or connected to some type of implanted access port or drug reservoir. In either case, PCEA is achieved by using a pump to deliver the drug through the catheter and into the area directly surrounding the spinal cord. Administration of drugs into the epidural space is obviously more difficult than simple intravenous delivery using a peripheral vein. Epidural delivery does, however, offer advantages in terms of providing more effective analgesia with a smaller amount of drug. For instance, it is estimated that epidural morphine is 5 to 10 times more potent than IV morphine, indicating that less drug needs to be administered by the epidural route to achieve adequate analgesia.17 This fact makes sense, considering that PCEA administers the drug closer and more directly to the spinal cord compared with the amount of drug that must be added to the bloodstream via PCIA so that enough medication eventually reaches the spinal cord via the systemic circulation. Likewise, there have been numerous studies that directly compared PCEA with other parenteral administration routes, including PCIA. Although these studies varied in the type of analgesic drugs used and the clinical indication (i.e., pain control following various types of surgery), they routinely found that PCEA provided superior pain control without a significant increase in side effects.6,26,40,49 By improving pain control after surgery, PCEA can also facilitate early recovery and rehabilitation in situations such as total knee arthroplasty.24

Implanted Pump

Transdermal PCA
Patient controlled transdermal analgesia (PCTA) is one of the newest variations on PCA. PCTA uses a delivery system consisting of a small patch that is approximately the size of a credit card.29,45 This patch is adhered to the patients skin, usually on the arm or upper chest. The patch is impregnated with an opioid such as fentanyl, and the patient can self-administer a

FIGURE 173 Schematic i